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48th Annual Meeting and Exposition of the American Society of Hematology

Orlando, Florida / December 9-12, 2006

Mycosis fungoides and its leukemic variant, Sezary syndrome, are the most common types of cutaneous T-cell lymphomas (CTCLs). Both arise when T-cells that normally guard the skin lose their ability to undergo programmed cell death. Patients who have only skin involvement have a survival curve similar to age-matched controls but as the tumour burden increases, prognosis worsens. Skin-directed therapies are used to treat early disease but responses are not durable and there is a real need for better therapies, observed Dr. Madeleine Duvic, Professor of Internal Medicine and Dermatology, University of Texas M.D. Anderson Cancer Center, Houston.

Poised to fulfill this unmet need is a new class of agents known as histone deacetylase (HDAC) inhibitors. Several are in development but vorinostat is currently approved for the treatment of CTCL by the U.S. Food and Drug Administration and results to date indicate there is real hope for improved treatment of advanced CTCL. As an inhibitor of classes I and II HDAC, vorinostat inhibits both tumour growth and angiogenesis and has been shown to have broad preclinical anti-tumour activity in a number of cancers, including CTCL. In an initial phase I study carried out at the M.D. Anderson Cancer Center, both oral and intravenous (i.v.) formulations were found to be well tolerated but bioavailability was better with oral dosing. A subsequent phase II study carried out by Dr. Duvic’s group involved a total of 33 patients, 29 of whom had stage IIB disease or greater. All patients were heavily pretreated with a mean number of five prior therapies.

An objective overall response rate to oral vorinostat 400 mg/day was achieved in eight of the 33 patients (24%) of the cohort, at a median time to response of 83.5 days and a median duration of response of 106 days. Importantly, particularly for Sezary syndrome patients for whom itching is the chief complaint, a 50% reduction in pruritus was achieved in 23 patients (70%) of the group overall. Grade 3 to 4 thrombocytopenia was seen in 21% of the cohort, while anemia and deep vein thrombosis were seen in 9% of the group, with pulmonary embolism and hypotension and dehydration occurring in 6% of patients.

A second phase II multicentre trial also reported here by Dr. Duvic involved 74 patients with either mycosis fungoides or the Sezary syndrome, where vorinostat 400 mg/day was received orally with food. The cohort was again heavily pretreated with a median of three prior therapies and had refractory advanced disease. In this cohort, the overall response rate was 29.7% and the median time to response was approximately 55 days. Valuable long-lasting responses were also observed in this trial, where the median duration of response and time to progression (TTP) had not yet been reached at the time of the presentation but which were estimated to be approximately six and 9.8 months, respectively, for all patients.

Over three-quarters of patients in this phase II trial also achieved a beneficial reduction in their skin disease, although they did not achieve the primary end point of a 50% or better reduction in skin symptoms lasting for at least four weeks. Again, pruritus was reduced in 43% of patients who responded to treatment as well as in 25% of patients who did not achieve an objective skin response. “Importantly, response to prior therapy was not predictive of response to vorinostat,” Dr. Duvic emphasized.

Combined safety data on a total of 107 patients involved in the phase II studies—86 of whom received the 400-mg dose—indicate that grade 3 fatigue was among the more common side effects seen with HDAC inhibitors, as were gastrointestinal (GI) side effects. Thrombocytopenia was the most common hematologic toxicity but in general, the compound was well tolerated, Dr. Duvic indicated. “It is also conveniently dosed once daily with food and avoids the need for catheters, which are frequently associated with sepsis in these patients,” she added.

Currently, no biomarker that predicts response to the HDAC inhibitors has been validated. However, in the larger phase II study, investigators observed that treatment with vorinostat induced T-cell apoptosis and reduced microvessel density in CTCL lesions. Its mechanism of action appeared to be specific for the malignant cell itself rather than normal cells, Dr. Duvic explained. Investigators have also observed that over 80% of patients who did respond to vorinostat had demonstrable shifts from nuclear phosphorylated stat-3 to the cytoplasm after four weeks of treatment compared with only about 20% of non-responders, suggesting that relevant biomarkers predicting response to this new class of agents may eventually help guide therapeutic decision-making.

Emerging Options

Another HDAC inhibitor, depsipeptide, is currently under development. Early results suggest that it also has broad preclinical anti-cancer activity and that it is likely to prove effective in CTCL as well. In one multicentre phase II study evaluating depsipeptide, interim results indicated that the agent, at a dose of 14 mg/m² i.v. delivered on days 1, 8 and 15 every 28 days for up to six cycles, produced an overall response rate of 36% in a cohort of 64 patients, two of whom achieved a complete response (CR) and eight of whom achieved a partial response (PR).

Safety and tolerability data of depsipeptide also indicated that the incidence of grade 3 and higher toxicities is low and are mainly GI in nature. Discontinuation rates due to adverse events were also low in this study. As discussed by Dr. Paul Hamlin, Lymphoma Service, Memorial Sloan-Kettering Cancer Center, New York, the HDAC inhibitors appear to be active in other types of hematologic malignancies as well. For example, both vorinostat and depsipeptide have been shown to have preliminary activity in Hodgkin’s lymphoma, diffuse large B-cell lymphoma (DLBCL) and peripheral T-cell lymphoma. “To date, some of the best responses for the HDACs have been seen in patients with T-cell lymphomas,” Dr. Hamlin commented. Studies are ongoing in which the potential activity of HDAC inhibitors given either as a single agent or in combination with other targeted agents is being evaluated and may extend their use to other lymphoproliferative malignancies other than CTCL. For example, clinical responses to oral vorinostat have been reported in some patients with relapsed or refractory leukemias as well as myeloid proliferative disorders (MPD).

Other Leukemias

In a phase I trial under lead investigator Dr. Andrey Loboda, Whitehouse Station, New Jersey, 41 patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML) in either accelerated phase (AP) or blast crisis (BC), or MPD received a total daily dose of vorinostat ranging from 30 to 1000 mg for 14 days of treatment followed by seven days of rest. Peripheral blood and bone marrow samples were obtained prior to treatment and after administration. Analysis of histone acetylation in blood and bone samples by ELISA showed that acetylation of histone H3 was rapidly induced in all evaluated patients regardless of the dose level or response, with acetylation levels returning to baseline during the week of rest prior to the next cycle. Results also showed that oral vorinostat led to decreased expression levels of proliferation-associated genes in patients who later achieved hematologic improvement or response, which was consistent with decreased peripheral blood blast counts observed in responders.

As the authors suggested, use of these predictive efficacy and resistance signatures in patients prior to initiating treatment may allow for the exclusion of more than 50% of patients who would not benefit from treatment with a HDAC inhibitor.

Managing Resistance

Imatinib, a first-generation tyrosine kinase inhibitor (TKI), has proven highly successful in the management of CML but not all patients respond to first-line imatinib and progression-free survival rates among those who do not achieve a complete cytogenic response are significantly shorter than for those who do. Moreover, after four years, 73% of patients in AP and 95% of patients in BC will be resistant to imatinib. Second-generation TKIs can often overcome this resistance but not when it is caused by the T315I mutation, whose presence or development currently precludes the use of all currently available TKIs.

As noted by lead author Dr. Franck Nicolini, Édouard Herriot Hospital, Lyon, France, approximately 50 different Bcr-Abl mutations have been described and are responsible for different levels of clinical resistance. However, the T315I mutation is the most frequent mutation identified in CML patients and is responsible for very poor outcomes.

In a retrospective analysis of 27 CML patients who harboured the T315I mutation, Dr. Nicolini and colleagues found that the median time for progression from the first day of imatinib administration was only 13 months, regardless of the phase of the disease on identification of the T315I mutation. Median overall survival from the first day of imatinib use was also short at 17.5 months for advanced phases of the disease and 42.5 months for chronic-phase patients.

Thus, as Dr. Nicolini and colleagues concluded, onset of the Bcr-Abl T315I mutation is always responsible for disease progression and poor survival, thereby underlying the need for alternative treatments. Fortunately, several new assays now appear to be able to successfully and rapidly detect the T315I mutation.

As reported by Dr. Michael Heinrich, Oregon Health and Science University Cancer Institute, Portland, researchers have now developed a T315I mutation detection assay and have tested it under a variety of conditions. To date, the new assay’s sensitivity and specificity are both 100%, as researchers reported. Using patient-derived samples, they were able to successfully genotype these samples even if they contained as few as 20 to 50 Bcr-Abl transcripts. “Appropriate detection of the [T315I] mutation is essential to optimal management of patients with imatinib resistance and may be useful for clinical trials of agents that target patients with this mutation,” investigators stated. A separate PCR-based assay similarly proved successful in helping detect low levels of mutations, including the T315I and the E255K mutations, in twice as many patients as was possible with direct sequencing.

Aurora Kinase Inhibition

As is clearly the case for the management of advanced CTCL, there is a similarly pressing need for new therapies that offer CML patients another chance of remission following the development of TKI resistance. As described by Dr. Donald Bergstrom, Upper Gwynedd, Pennsylvania, the aurora kinase inhibitors appear poised to close this therapeutic gap. As the first in its class, MK-0457 is a small molecule kinase inhibitor that targets all three aurora kinases, FLT3, JAK2 and Bcr-Abl, including the T315I mutant of Bcr-Abl, which mediates high-level resistance to imatinib, dasatinib and nilotinib.

MK-0457 also induces apoptosis at nanomolar levels in a wide range of tumours, has minimal toxicity in animal models and has no effect on non-cycling cells, Dr. Bergstrom noted. The molecule also recognizes the active conformation of the kinase domain and this leads to rapid stabilization of the inactive conformation. Compared with imatinib and dasatinib, test results indicate that there is clear inhibition of both wild-type Bcr-Abl as well as the Bcr-Abl T315I mutation.

In an analysis of peripheral blood samples from CML and ALL patients with the T315I mutation, Dr. Bergstrom and colleagues observed “marked decreases in the level of phosphor-CRKL” at day 5. “When we looked at patients treated with the >20 mg/m²/hr dose, we saw a striking correlation between patients who achieved a major hematologic or major cytogenic response and decreases in phosphor-CRKL,” Dr. Bergstrom told the audience.

In that objective responses have also been observed in patients who had no demonstrable Bcr-Abl inhibition with MK-0457 treatment, “This suggests that inhibition of aurora kinase may also contribute to the clinical efficacy of [the molecule] in CML and ALL patients with the Bcr-Abl T315I mutation,” Dr. Bergstrom said.

Clinical evaluation of MK-0457 is still in its early stages but results to date are promising. A phase I study was initiated in 2005 at the M.D. Anderson Cancer Center during which the safety and tolerability of a five-day continuous i.v. infusion protocol was evaluated, with MK-0457 being given every 14 to 21 days.

A total of 40 evaluable patients have now received treatment with MK-0457 at dose levels ranging from 8 to 32 mg/m²/hr. Patients included in this early trial had CML, ALL, AML as well as some JAK2-positive patients with MDP. All CML patients who were treated with the molecule had received imatinib as prior therapy and all patients had failed a second-generation TKI. Of the 15 patients with CML, 11 had the T315I mutation, as did one of two ALL patients.

“Objective responses were observed in 11 out of 14 currently evaluable patients with CML and all 11 responding patients had the T315I mutation,” noted Dr. Michael Mauro, Associate Professor of Medicine, Oregon Health and Science University. In addition, one patient with T315I Abl mutant Philadelphia chromosome-positive ALL achieved an objective response, as did six out of eight evaluable patients with JAK2-positive refractory MPD. Treatment was also extremely well tolerated, the primary toxicity being dose-dependent myelosuppression in the form of neutropenia. The only potential drug-related non-hematological toxicities were lipase elevations but this occurred in only two patients and was not considered a dose-limiting toxicity. Mild alopecia and possibly moderate mucositis may also occur but these potential treatment-related adverse events need to be confirmed by additional studies.

In a presentation given on behalf of the lead investigator of this trial, Dr. Jamie Freedman, Upper Gwynedd, Pennsylvania, also noted that all objective responses—including hematological, cytogenic or molecular—occurred at or above the 20-mg/m²/hr dose and patients entering ongoing accrual into the study will receive the 36-mg/m²/hr dose.

Summary

Progress has been made towards improving outcomes for patients with a variety of hematologic malignancies but therapeutic gaps remain. In the treatment of CTCL, for example, systemic therapies have not led to adequate disease control and there has been little to offer patients with advanced disease. Thus, the arrival of a new class of agents, the HDAC inhibitors offers the first real hope for patients with advanced CTLC. Similarly, the TKIs have been highly successful in early CML but as the disease becomes more advanced, resistance is common and once patients develop the T315I mutation, no further medical therapy is currently available. The arrival of the aurora kinase inhibitors now in clinical development will provide another opportunity of inducing further remissions and of prolonging survival for CML patients with resistant disease and possibly for those with other hematologic malignancies as well.