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Leukemia Insights Spring 2011

Leukemia Insights Spring 2011

INSIGHTS VOL. 16 • NO. 1 SPRING 2011 Updates of New Strategies in Chronic Myelogenous Leukemia

INTRODUCTION However, despite the major advances in therapy, there is room for improving CML management. Presently, there Imatinib revolutionized the treatment of Philadelphia- are clinical trials addressing the different stages of the . positive (Ph+) chronic myeloid leukemia (CML) and Some of the available clinical trials are reviewed here. established targeted BCR-ABL inhibitors as the standard of care1. The 8-year follow-up of the phase 3 IRIS trial reported a cumulative best complete cytogenetic response FRONTLINE THERAPY (CCyR) of 83% and an estimated overall survival of 93% Nilotinib Studies (CML-related deaths) in patients with newly diagnosed In 2005, we initiated a phase II study assessing chronic phase CML (CML-CP)2. However, 10% of those nilotinib in the frontline setting. This study included 67 patients who achieve CCyR will relapse. Additionally, patients with Ph+ CML-CP and seven patients with 17% of imatinib-treated patients do not achieve CCyR CML-AP. Each patient was diagnosed within 6 months of while 8% show intolerance to imatinib3. enrollment and was either untreated or treated with only Second-generation tyrosine kinase inhibitors (TKIs) hydroxyurea, , or imatinib 400 mg once daily for are more potent BCR-ABL inhibitors with demonstrated a maximum of 1 month prior to study entry11. The efficacy in patients resistant to or intolerant of imatinib4-8. patients were treated with nilotinib 400 mg twice daily. Dasatinib and nilotinib, each with well-established safety The primary endpoint of the trial was a major molecular profiles9, 10, are approved in this setting and are active response (MMR) at 12 months defined as a BCR-ABL against all BCR-ABL mutations except T315I. The percentage ratio (International Scale) ≤ 0.1%. The increased potency of these agents makes them attractive secondary endpoint was a CCyR at 12 months. candidates for use in the frontline setting. At a median follow-up of 17.3 months, evaluable Other non-TKIs are in development. T315I mutations CML-CP patients had achieved a CCyR and MMR of are emerging with increasing frequency, and patients with 93% and 81% respectively. Responses were rapid and these mutations do not respond to current TKIs. Several durable. At 3 and 6 month time points, CCyR was ongoing studies of tyrosine kinase inhibitors with activity achieved in 78% and 96% of patients respectively. against T315I are showing positive results. Likewise, MMR was achieved in 42% and 75% of patients. At 24 months, 93% and 79% of patients maintained In This Issue CCyR and MMR respectively, and 20% of patients achieved a complete molecular response (CMR), an 1 Introduction increase from 11% at 12 months. One patient, who dis- continued nilotinib because of intolerance after achieving 1 Frontline Therapy a CCyR, progressed to blast phase (BP) after an allogeneic stem cell transplant. 3 New Agents Post TKI Failure In all patients, including the seven patients with CML- AP, grade 3/4 nonhematologic AEs were uncommon. 4 Eradicating Residual Disease Elevations of bilirubin, lipase, and amylase occurred at rates of 8%, 6%, and 3% respectively. Grade 3/4 hemato- 5 Monitoring Response and Resistance logic AEs included (12%), to Therapy (11%), and (5%).

6 Management of Side Effects

7 Advanced Phase Disease (continued on page 2)

7 The Potential for Cure

8 Treatment Priorities Based on the results of our trial as well as the (defined as a complete molecular response of ≤ 0.0032% GIMEMA trial12, ENESTnd, a phase 3 randomized, open- BCR-ABL IS) with nilotinib 300 mg twice daily (13%) label, multicenter study comparing the efficacy and safety and nilotinib 400 mg twice daily (12%) than with ima- of nilotinib with imatinib in patients with newly diagnosed tinib (4%). These higher responses were also associated CML, was initiated15. The trial included 846 patients with significantly fewer progressions with nilotinib than randomly assigned 1:1:1 to nilotinib 300 mg twice daily with imatinib. (n = 282), nilotinib 400 mg twice daily (n = 281), or Grade 3/4 nonhematologic AEs were uncommon across imatinib 400 mg/day (n = 283). MMR at 12 months was all three arms of ENESTnd, and all occurred at rates of ≤ the primary endpoint. 1%, except for rash which occurred at a rate of 3% in the The MMR rate at 12 months was significantly higher nilotinib 400 mg twice daily arm. No instances of QTcF for nilotinib 300 mg twice daily (44%, P < 0.0001) and prolongation > 500 msec were observed in any of the nilotinib 400 mg twice daily (43%, P < 0.0001) than for treatment arms. Grade 3/4 laboratory abnormalities were imatinib (22%). The best cumulative MMR rates by 12 uncommon in the nilotinib arms. Rates of grade 3/4 ane- months were also significantly higher for nilotinib 300 mg mia and neutropenia were higher in the imatinib arm of twice daily (55%, P < 0.0001) and nilotinib 400 mg twice the trial, whereas grade 3/4 thrombocytopenia was more daily (51%, P < 0.0001) than for imatinib (27%)15. frequently observed in the nilotinib arms. Likewise, cumulative rates of CCyR by 12 months were All efficacy endpoints assessed continued to be superior also significantly higher for nilotinib 300 mg twice daily for nilotinib with a minimum of 24 months of follow-up13. (80%, P < 0.0001) and 400 mg twice daily (78%, P < Achievement of MMR by 24 months was significantly 0.0005) than for imatinib (65%). Responses were rapidly higher for nilotinib 300 mg twice daily (71%, P < 0.0001) achieved with nilotinib. Nilotinib dosing schedules of 300 and nilotinib 400 mg twice daily (67%, P < 0.0001) compared mg twice daily and 400 mg twice daily showed 6 month with imatinib (44%). Achievement of CMR continued to be MMR rate of 33% and 30%; subsequent 9 month MMR significantly higher for nilotinib 300 mg twice daily (26%, rates showed an increase to 43% and 38% respectively. On P < 0.0001) and nilotinib 400 mg twice daily (21%, P = the other hand, imatinib demonstrated 6 and 9 month 0.0004) compared with imatinib (10%). The safety and MMR rates of 12% and 18% respectively. In addition, tolerability profiles of nilotinib and imatinib were more patients achieved undetectable levels of disease unchanged with longer follow-up.

Nilotinib for Newly Diagnosed CML-CP Phase of Study Number of Patients (n) Dose CCyR % MMR % II 67 400 mg twice daily 93 81

II 73 400 mg twice daily 96 85 282 300 mg (nilotinib) 80 44 III 281 400 mg (nilotinib) 78 43 283 400 mg (imatinib) 65 22

Dasatinib Studies The design of our dasatinib trial in the frontline setting At a median follow-up of 24 months, 98% and 71% of was similar to the nilotinib phase II study. The dasatinib patients evaluable at 12 months had achieved a CCyR and study included 62 patients with Ph+ CML-CP diagnosed an MMR respectively. Responses were also rapid. At 3 within 6 months of enrollment. The patients were either months, CCyR and MMR rates were 81% and 24%; subsequent untreated or treated with only hydroxyurea, anagrelide, or 6 month data showed an increase to 94% and 63% imatinib 400 mg/day for a maximum of 1 month prior to respectively. At 24 months, CCyR and MMR rates were study entry14. The dasatinib trial included a 100 mg/day 84% and 87%. At 12 and 24 months, rates of CMR were arm (n = 31) and a 50 mg twice daily arm (n = 31). respectively 7% and 6% in evaluable patients. Similar to the nilotinib trial, the primary and secondary Additionally, progression to AP/BP has yet to be seen in endpoints of the dasatinib trial were MMR and CCyR the patients. Grade 3/4 nonhematologic AEs were rates at 12 months, and the response definitions were uncommon and included (6%), joint and muscle identical to those in the nilotinib trial. pain (6%), and dyspnea (5%). Pleural effusions were

2 observed in 13% of patients, with only one instance of a The DASISION trial demonstrated similar results with grade 3 pleural effusion. Grade 3/4 hematologic AEs a minimum of 18 months of follow-up16. Overall cumulative included neutropenia (21%), thrombocytopenia (10%), achievement of CCyR was higher on dasatinib (85%) and anemia (6%). compared with imatinib (80%). Overall cumulative Subsequently, DASISION, a phase 3 randomized, achievement of MMR was significantly higher on dasatinib open-label, multicenter study comparing the efficacy and (57%, P = 0.0002) compared with imatinib (41%). Rates safety of dasatinib 100 mg once daily with that of of CMR were numerically higher on dasatinib (13%) imatinib, was initiated15. 519 patients with newly compared with imatinib (7%) at any time. The safety diagnosed CML-CP were randomly assigned 1:1 to either and tolerability profiles of dasatinib and imatinib were dasatinib 100 mg once daily (n = 259) or imatinib 400 similar with longer follow-up. mg/day (n = 260). Confirmed CCyR by 12 months was the primary endpoint of the study. The best cumulative Taken together, the results from all trials of nilotinib MMR rate by 12 months was significantly higher for and dasatinib in the frontline setting demonstrate that dasatinib (46%, P < 0.0001) than for imatinib (28%). second-generation TKIs provide faster response rates, Best cumulative rates of CCyR by 12 months were also deeper responses, and lower rates of AP/BP progression significantly higher for dasatinib (83%, P < 0.001) than when compared with imatinib. As a consequence, nilotinib for imatinib (72%). Along with these higher response and dasatinib, in addition to imatinib, are considered front- rates, there were fewer progressions to AP/BP with line options for patients with newly diagnosed CML-CP. dasatinib (1.9%) than with imatinib (3.5%). With the main advantage of offering free drugs to Grade 3/4 nonhematologic AEs were uncommon across participants, our single-arm, phase II trials of nilotinib both treatment arms. Pleural effusions were mostly grade and dasatinib are still open and accruing new patients. 1-2 and occurred in 10% of patients treated with The single-arm, phase II study of nilotinib is open as dasatinib. Rates of grade 3/4 anemia and thrombocytopenia well for patients with newly diagnosed accelerated phase were higher on dasatinib than imatinib. Overall, disease. In addition, these studies are looking at issues of discontinuations due to drug-related AEs occurred in adherence to therapy, quality of life, and the impact of 5% of patients in the dasatinib arm and 4% of patients therapy in bone . in the imatinib arm. Dasatinib for Newly Diagnosed CML-CP Phase of Study Number of Patients (n) Dose CCyR % MMR % II 62 100 mg once daily 98 71 259 100 mg (dasatinib) 77 46 III 260 400 mg (imatinib) 67 28

NEW AGENTS TO TREAT CML POST Ponatinib (AP24534) TKI FAILURE Ponatinib is one of the most promising agents for treat- ment of T315I mutation. Ponatinib is an orally available Multiple strategies to overcome TKI failure are under multi-TKI designed using a structure-based approach as a investigation. Post imatinib failure, nilotinib and dasatinib pan-BCR-ABL inhibitor19. Ponatinib potently inhibits the are both FDA approved and continue to show sustained enzymatic activity of BCR-ABL-T315I, the native enzyme, efficacy, with almost half of patients with imatinib failure and all other tested mutants. It also prevents the emer- being able to achieve a CCyR17-18. However, in patients in gence of resistant mutants at concentrations of 40 nM. In whom imatinib has failed because of the presence of the a phase 1 of AP24534 at doses from 2-60 mg T315I mutation and in patients who have failed 2 TKIs, in 60 patients with CML (44 with CP, 7 AP and 9 BP), there are no currently available standard options. For these complete hematologic response (CHR) was achieved or patients, new agents are being developed and early results maintained in 95% of patients treated in CP; major hema- seem promising. tologic responses were also achieved in 35% of patients treated in advanced stages of the disease19. More impor- tantly, 25 of 38 (66%) evaluable patients treated in CP achieved a MCyR, including 20 (53%) CCyR. All 9

3 patients with T315I mutations in CP achieved MCyR Abnormalities of the JAK-STAT pathways have been with 89% of them achieving CCyR. The most common described in a variety of , and their inhibition drug-related adverse events were elevations of lipase can be a goal for leukemia therapy. Recent reports suggest and amylase at a dose of 60 mg daily. Grade 3 or 4 that JAK2 activation is critical in maintaining the leukemic thrombocytopenia occurred in 9% of patients, with no stem cell in CML. grade 3-4 drug-related neutropenia. Currently, our institution INCB018424 phosphate is an inhibitor of the JAKs is testing Ponatinib in a phase II, multinational study that is currently being developed for treatment of focusing on patients who have failed dasatinib and/or myeloproliferative disorders21. Our current study is examining nilotinib therapies including a subset of patients with the potential role of this drug in CML. Patients with CML the T315I mutation. who are resistant to at least 2 TKIs and have no standard stem cell transplant option are eligible as well as patients DCC-2036 with relapse/refractory CML in blast crisis. While second generation BCR-ABL inhibitors dasatinib and nilotinib both inhibit many imatinib-resistant mutations, Hedgehog Inhibitors neither drug is effective against the T315I mutation. Extensive evidence has been developed for a role for DCC-2036 is a new tyrosine kinase inhibitor that Hedgehog (HH) signaling, including the Smoothened overcomes imatinib resistance by binding to a different transmembrane protein (Smo), in the maintenance and domain on the BCR-ABL protein thus avoiding interaction proliferation of CML stem cells. Using a variety of models, with the mutated regions most commonly associated with activation of Smo was demonstrated in Bcr-Abl+ cells, resistance. DCC-2036 retained full potency against the and their proliferation was shown to be more dependent T315I mutant kinase in preclinical studies and therefore on Smo than that of normal hematopoietic stem cells22. warrants testing in patients who have failed prior TKI Conversely, inhibition of HH signaling reduced self-renewal therapies or who have the T315I mutation and are diagnosed , in vivo, and in murine retransplantation models. with either Ph+ CML or Ph+ ALL. DCC-2036 is also Additionally, reduction of stem cells (defined as clonal active against wild type BCR-ABL and other mutants progenitors developing during long-term culture) by Smo commonly seen after imatinib failure20. Early results in our inhibition was demonstrated in CML patient samples22. phase I clinical trial of DCC-2036 suggest evidence Recently, the importance of Smo signalling in CML stem of clinical benefit. cell function was independently demonstrated23; constitutive Smo expression increased whereas conditional deletion INCB018424 reduced this population. In a recent preclinical study, the Abnormalities of Janus Kinase (JAK) function have combination of nilotinib plus the Smo inhibitor LDE225 been associated with a number of hematological disorders. was reported to provide supra-additive inhibition of primitive For example, chromosomal translocations resulting in CML stem cells24. Thus, the combination of TKI with HH TEL-JAK2 constructs lead to the constitutive activation of inhibitor provides an important opportunity to potentially STAT5, IL-3-independent cellular proliferation, and cure patients with CML. The sequential combination of leukemogenesis. The translocation t(9;12)(p24;p13) TKI and HH inhibitor is planned at our institution for results in the fusion of the kinase catalytic region of JAK2 patients with minimal residual disease and/or suboptimal with the transcription factor TEL generating the response to TKI. We are currently conducting a phase I constitutively active TEL-JAK2. Similarly, infection with study of the hedgehog inhibitor PF-04449913 for patients oncogenic viruses such as type I human T-cell lymphotrophic with CML (and other hematologic malignancies) who virus and Abelson murine leukemia viruses results in have failed prior therapy. The first portion of the study enhanced kinase activity of Jaks, possibly accounting for tests this agent by itself. In the second portion of the their leukemogenic potential. study, we will combine this agent with a tyrosine kinase inhibitor.

ERADICATING RESIDUAL DISEASE Despite extraordinary progress, true cure of CML is not Studies assessing the combination of TKIs with promising generally achieved by Abl kinase inhibitors. TKIs are agents are to be initiated. If successful, this strategy could potent inhibitors of Bcr-Abl kinases, resulting in rapid lead to the safe, permanent discontinuation of therapy in reduction of the majority of cells carrying the Ph chromosomal patients with a good response. marker. However, suppression of Abl-driven hematopoiesis may be insufficient to eradicate quiescent stem cells.

4 Omacetaxine provides a distinct therapeutic approach from TKI alone Omacetaxine (homo-harringtonine), a small molecule and may exert an antileukemic effect in CML stem cells inhibitor of ribosomal processes that affects the activity of that are resistant to all TKIs. A combination single-arm MCL-1, c-myc, and cyclin D1, acts independently of trail is about to be initiated at our institution for patients Bcr-Abl activity25. This agent has shown activity in with persistent minimal residual disease or suboptimal patients with the Bcr-Abl T315I mutation and in patients response to TKI therapy. who have failed two TKIs26-27. In addition, there is growing evidence suggesting synergy with TKI and potential activity PEG-interferon of omacetaxine against the dormant stem cells28. Historically, interferon has been a very useful drug in Therefore, omacetaxine may be additive or synergistic CML, and patients have been cured. Imatinib proved to with TKI; such a combination is an attractive strategy to be superior and better tolerated thus displacing interferon eliminate the leukemic stem cell which is insensitive to all as the initial therapy of CML. However, interferon has available tyrosine kinase inhibitors. A phase II, single-arm important anti-leukemia activity, immunomodulatory trial combining omacetaxine and TKI in patients with properties, and a possible role in eradicating the leukemic suboptimal response to TKI with persistent minimal stem cell, making it potentially useful for patients with residual disease is to be initiated at our institution. CML. Pegylated interferon is considerably better tolerated than regular interferon. It is administered only once weekly Hypomethylating agents and has better anti-leukemia activity. We are currently Aberrant DNA methylation can lead to carcinogenesis exploring the addition of pegylated interferon for the by silencing tumor suppressor or other critical genes29. In management of minimal residual disease in two settings: CML, DNA methylation increases in concert with disease 1) Single agent: For patients who have had a good progression30. Reversal of DNA methylation has been response to tyrosine kinase inhibitors (at least a complete investigated as a target for cancer therapy31. We have cytogenetic response) but have not achieved a major previously shown that , a hypomethylating molecular response or complete molecular response, we agent, has single-agent clinical activity in CML32-33, will add pegylated interferon at low doses to the ongoing including imatinib-resistant cases. In addition, we showed TKI therapy to monitor whether all evidence of disease that combination therapy with decitabine and imatinib may be eradicated. was well tolerated and active in advanced phase CML 2) Combination with PR1 vaccine: This vaccine has without BCR-ABL kinase mutations34. Interestingly, we shown some exciting preliminary results eradicating leukemic and others have demonstrated that the synergy between cells through a specific immune mechanism. By combining decitabine and a TKI such as imatinib depends on residual this vaccine with pegylated interferon, we will explore sensitivity to imatinib34-35. Thus, in patients completely whether a more specific immune recognition leading to resistant to TKI, adding decitabine may not be sufficient eradication may be achieved in patients who have failed to to reverse resistance. As such, this synergy may be optimal achieve a major molecular response or complete molecular in patients who were treated with TKI and have persistent response. The vaccine is added while patients continue with minimal residual disease. Such a combination clearly their standard TKI therapy.

MONITORING RESPONSE AND RESISTANCE TO THERAPY IN CML Several monitoring methods are available to assess response. Additionally, PB FISH can also be used for response and resistance to therapy in CML: 1) cytogenet- long-term monitoring (e.g. every 6-12 months,) although ics, 2) FISH, 3) qualitative PCR, and 4) mutational stud- it would not allow for detection of chromosomal ies. Details of advantages and disadvantages of each are abnormalities in Ph-negative metaphases. detailed in a recent review36. 3) In cytogenetic CR, monitor with QPCR every 6 months. Aim for BCR-ABL/ABL ratio of < 0.1% in the A simple way of monitoring patients outside the international scale (ie, 3-log reduction from standardized context of a protocol is as follows: baseline). For patients in CCyR, do not react drastically to 1) for morphology and cytogenetics rises in transcript levels unless consistent with loss of pretreatment, at 6 and 12 months to assess imatinib major molecular response (BCR-ABL/ABL ratio > 0.1% in response, then every 1-2 years if stable CCyR the international scale) and with a 1-log increase. In these 2) Peripheral blood FISH can help assess the cytogenetic cases, resort to lower-risk treatment changes, such as

5 increasing the imatinib dose, as opposed to higher-risk show mutations. A T315I mutation should lead to treatment changes, such as allogeneic transplantation. consideration of allogeneic stem cell transplant. The 4) In standard practice, do not perform mutational mutations IC50 to a particular agent is a better guide to analysis at pretreatment or in patients responding to imatinib. select therapy. For example, most P-loop mutations respond Mutational studies are best done only in patients already well to dasatinib while mutations V299L and F317L on imatinib who are demonstrating either cytogenetic or respond well to nilotinib. Please consult with a CML hematologic relapse. About 50% of these patients will expert in such situations.

MANAGEMENT OF SIDE EFFECTS Some of the most common adverse events observed with tyrosine kinase inhibitors and suggested management options37 are listed in the following table.

Management of the Most Common Nonhematologic Adverse Events Observed During Therapy with Tyrosine Kinase Inhibitors

Adverse Event Management • Antiemetics as needed Nausea/vomiting • Take imatinib with food, abundant fluids • Use loperamide or diphenoxylate and atropine • Diuretics as needed Peripheral edema • Monitor electrolytes if diuretics are used • Steroid-containing cream Periorbital edema • Surgical management frequently followed by recurrence • Symptomatic management (e.g. diphenhydramine), topical Skin rash or systemic steroids • Adequate sun protection • Quinine or tonic water; calcium gluconate Muscle cramps • Electrolyte replacement as needed • Nonsteroidal antiinflammatory agents Arthralgias, bone pain • Nonsteroidals not recommended for patients taking dasatinib • Treatment interruption until recovery to grade 1 or less, then Elevated transaminases reduce dose • Treatment interruption o Common with nilotinib among patients with Gilbert’s Hyperbilirubinemia syndrome, with minimal clinical consequences • Monitor • Clinical evaluation for signs or symptoms of pancreatitis Elevated lipase/amylase o If no evidence of pancreatitis, continued monitoring Hypophosphatemia • Replacement therapy; monitor closely • Assess before starting therapy and correct any electrolyte abnormalities QTc prolongation • Avoid coadministration of other agents that may prolong QTc • Consider alternative therapies in patients with signifi cant QTc prolongation despite these measures • Treatment interruption, diuretics Pleural effusion • Corticosteroids may be of benefi t to some patients • Thoracentesis when unresponsive or with major symptoms

6 The most common adverse event seen with tyrosine tiated at the same dose; however, a dose reduction is kinase inhibitors is myelosuppression, with grade 3 or 4 recommended if recovery takes longer than 2 weeks. neutropenia (absolute neutrophil count < 1 x109/L) and Hematopoietic growth factors –filgrastim for neutropenia, thrombocytopenia (platelet count < 50 x 109/L) in up to epoetin alfa for anemia, and oprelvekin for thrombocytopenia- 30% of patients, and anemia in 5% to 15% of patients. have been reported to benefit patients with recurrent Myelosuppression most often occurs early during the myelosuppression that limits proper administration of course of therapy (first 2-3 weeks) and is transient. For therapy38. However, the long-term safety of this approach those patients who develop grade 3 or 4 neutropenia or is not known. In the near future, a clinical trial will be thrombocytopenia, temporary interruption of therapy is initiated investigating the role of eltrombopag, an agonist recommended37. Therapy can resume once the counts of the c-mpl receptor, in correcting thrombocytopenia in recover to levels above those defining grade 3 cytopenias. patients whose CML therapy is limited by recurrent low If recovery occurs within 2 weeks, treatment can be reini- platelet counts.

ADVANCED PHASE DISEASE Despite the progress made in CML, the treatment of As the disease progresses, several new genetic and patients in accelerated or blast phase remains grossly epigenetic phenomena have been described. Of interest is unsatisfactory. Although some patients may respond to the increased methylation of critical genes. Hypomethylating treatment with single-agent TKI, the overwhelming agents have been shown to be active in patients with CML majority of responses are short-lived. This highlights the after failure to TKI and to have synergistic activity with need to develop additional treatment options for these TKI. We are initiating a trial in which patients with accel- patients. TKI in combination with standard erated or blast phase will receive therapy with decitabine has been attempted with some success but with combined with dasatinib. The objective of this trial is to considerable . determine whether such a combination may lead to more and more durable responses in this patient population.

THE POTENTIAL FOR CURE The impact of using more potent agents in the frontline setting in order to discontinue TKI therapy at a later time remains to be determined. The future of CML therapy may include early use of these potent agents, perhaps in combination with new molecules, to help more patients achieve CMR, leading to therapy discontinuation and cure.

For information on any of the clinical trials mentioned in this issue, please contact Drs. Jorge Cortes, Hagop Kantarjian, Elias Jabbour, or Alfonso Quintas-Cardama.

REFERENCES

1. Druker BJ, Guilhot F, O’Brien SG, Gathmann I, Kantarjian H, Gattermann N, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 2006;355(23):2408-17. 2. Deininger M , O’Brien SG , Guilhot F , Goldman JM , Hochhaus A , Hughes TP , et al. International randomized study of interferon vs STI571 (IRIS) 8-year follow up: Sustained survival and low risk for progression or events in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML- CP) treated with imatinib. Blood. 2009;114(22):462 [abstract 1126]. 3. O’Brien SG, Guilhot F, Goldman JM, Hochhaus A, Hughes T, Radich JP, et al. International randomized study of interferon versus STI571 (IRIS) 7-year follow-up: Sustained survival, low rate of transformation and increased rate of major molecular response (MMR) in patients (pts) with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) treated with imatinib (IM). Blood 2008;112:76. 4. Hochhaus A, Kantarjian HM, Baccarani M, Lipton JH, Apperley JF, Druker BJ, et al. Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy. Blood 2007;109(6):2303-9. 5. Hochhaus A, Baccarani M, Deininger M, Apperley JF, Lipton JH, Goldberg SL, et al. Dasatinib induces durable cytogenetic responses in patients with chronic myelogenous leukemia in chronic phase with resistance or intolerance to imatinib. Leukemia 2008;22(6):1200-6. 6. Shah NP, Kantarjian HM, Kim DW, Rea D, Dorlhiac-Llacer PE, Milone JH, et al. Intermittent target inhibition with dasatinib 100 mg once daily preserves efficacy and improves tolerability in imatinib-resistant and -intolerant chronic-phase chronic myeloid leukemia. J Clin Oncol 2008;26(19):3204-12.

7 REFERENCES (continued)

7. Kantarjian HM, Giles F, Gattermann N, Bhalla K, Alimena G, Palandri F, et al. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood 2007;110(10):3540-6. 8. Bruemmendorf TH, Cervantes F, Kim D, Chandy M, Fischer T, Hochhaus A, et al. Bosutinib is safe and active in patients (pts) with chronic phase (CP) chronic myeloid leukemia (CML) with resistance or intolerance to imatinib and other tyrosine kinase inhibitors. J Clin Oncol 2008;26(15_suppl):7001. 9. Sprycel (dasatinib) [package insert]. Princeton, NJ: Bristol Meyers Squibb Company; 2010. 10. Tasigna (nilotinib) [package insert]. Stein, Switzerland: Novartis Pharma Stein AG; June 2010. 11. Cortes JE, Jones D, O’Brien S, Jabbour E, Konopleva M, Ferrajoli A, et al. Nilotinib as front-line treatment for patients with chronic myeloid leukemia in early chronic phase. J Clin Oncol 2010;28(3):392-7. 12. Rosti G, Palandri F, Castagnetti F, Breccia M, Levato L, Gugliotta G, et al. Nilotinib for the frontline treatment of ph(+) chronic myeloid leukemia. Blood 2009;114(24):4933-8. 13. Saglio G, Kim DW, Issaragrisil S, le Coutre P, Etienne G, Lobo C, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med 2010;362(24):2251-9. 14. Hughes TP, Hochhaus A, Saglio G, Kim DW, Jootar S, le Coutre PD, et al. ENESTnd update: Continued superiority of nilotinib versus imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP). Blood 2010;116(21):94,95 [abstract 0207]. 15. Cortes JE, Jones D, O’Brien S, Jabbour E, Ravandi F, Koller C, et al. Results of dasatinib therapy in patients with early chronic-phase chronic myeloid leukemia. J Clin Oncol 2010;28(3):398-404. 16. 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A Phase 1 trial of oral ponatinib (AP24534) in patients with refractory chronic myelogenous leukemia (CML) and other hematologic malignancies: emerging safety and clinical response findings. Blood 2010;116(21):94,95 [abstract 0210]. 20. Van Etten RA, Chan WW, Zaleskas VM, et al. Switch Pocket Inhibitors of the ABL Tyrosine Kinase: Distinct Kinome Inhibition Profiles and in Vivo Efficacy in Mouse Models of CML and B-Lymphoblastic Leukemia Induced by BCR-ABL T315I. Blood. 2008; 112: 576. 21. Verstovsek S, Kantarjian H, Mesa RA, et al. Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N Engl J Med. 2010;363(12):1117-1127. 22. Dierks C, Beigi R, Guo G-R, et al. Expansion of Bcr-Abl-Positive Leukemic Stem Cells Is Dependent on Hedgehog Pathway Activation. Cancer Cell. 2008; 14:238–249. 23. Zhao C, Chen A, Jamieson CH, et al. Hedgehog signalling is essential for maintenance of cancer stem cells in. Nature. 2009; 458: 776-780. 24. Irvine DA, Zhang B, Allan EK, et al. Combination of the hedgehog pathway inhibitor LDE225 and nilotinib eliminates chronic myeloid leukemia stem and progenitor cells. Blood. 2009; 114:Abstract. 1428. 25. Quintás-Cardama A, Kantarjian H, Cortes J. Homoharringtonine, omacetaxine mepesuccinate, and chronic myeloid leukemia circa 2009. Cancer. 2009;115(23):5382-93. 26. Cortes-Franco J, Khoury HJ, Nicolini FE, et al. Safety and efficacy of subcutaneous-administered omacetaxine mepesuccinate in imatinib-resistant chronic myeloid leukemia (CML) patients who harbor the Bcr-Abl T315I mutation: results of an ongoing multicenter phase 2/3 study. Blood. 2009; 114:Abstract 644. 27. Cortes-Franco J, Raghunadharao D, Parikh P, et al. Safety and efficacy of subcutaneous-administered omacetaxine mepesuccinate in chronic myeloid leukemia (CML) patients who are resistant or intolerant to two or more tyrosine kinase inhibitors: results of a multicenter phase 2/3 study. Blood. 2009; 114:Abstract 861. 28. Marin D, Kaeda JS, Andreasson C, et al. Phase I/II trial of adding semisynthetic homoharringtonine in chronic myeloid leukemia patients who have achieved partial or complete cytogenetic response on imatinib. Cancer. 2005; 103:1850-1855. 29. Jones PA,Laird PW. comes of age. Nat Genet. 1999; 21: 163–167. 30. Nguyen TT,Mohrbacher AF,Tsai YC, et al. Quantitative measure of c-abl and p15 methylation in chronic myelogenous leukemia: biological implications. Blood. 2000; 95: 2990–2292. 31. Bhalla KN. Epigenetic and chromatin modifiers as targeted therapy of hematologic malignancies. J Clin Oncol. 2005; 23: 3971–3993.

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32. Kantarjian HM,O’Brien S,Cortes J, et al. Results of decitabine (5-aza 2’deoxycytidine) therapy in 130 patients with chronic myelogenous leukemia. Cancer. 2003; 98: 522–528. 33. Issa JP,Gharibyan V,Cortes J, et al. Phase II study of low-dose decitabine in patients with chronic myelogenous leukemia resistant to imatinib mesylate. J Clin Oncol. 2005; 23: 3948–3956. 34. Oki Y, Kantarjian HM, Gharibyan V, et al. Phase II study of low-dose decitabine in combination with imatinib mesylate in patients with accelerated or myeloid blastic phase of chronic myelogenous leukemia. Cancer. 2007;109(5):899-906. 35. La Rosee P,Johnson K,Corbin AS, et al. In vitro efficacy of combined treatment depends on the underlying mechanism of resistance in imatinib- resistant Bcr-Abl-positive cell lines. Blood. 2004; 103: 208–215. 36. Kantarjian H, Schiffer C, Jones D, Cortes J. Monitoring the response and course of chronic myeloid leukemia in the modern era of BCR-ABL tyrosine kinase inhibitors: practical advice on the use and interpretation of monitoring methods. Blood. 2008; 111:1774-1780. 37. Jabbour E, Deininger M, Hochhaus A. Management of adverse events associated with tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia. Leukemia. 2010 Sep 23. [Epub ahead of print] 38. Quintas-Cardama A, Kantarjian H, O’Brien S, et al. Granulocyte-colony-stimulating factor (filgrastim) may overcome imatinib-induced neutropenia in patients with chronic-phase chronic myelogenous leukemia. Cancer. 2004; 100:2592-2597.

List of Leukemia Service Attendings

ANDREEFF, MICHAEL (713) 792-7260 KANTARJIAN, HAGOP (713) 792-7026 BORTHAKUR, GUTAM (713) 563-1586 KEATING, MICHAEL (713) 745-2376 BURGER, JAN (713) 563-1487 KOLLER, CHARLES (713) 792-7747 CORTES, JORGE (713) 794-5783 KONOPLEVA, MARINA (713) 794-1628 ESTROV, ZEEV (713) 794-1675 KORNBLAU, STEVEN (713) 794-1568 FADERL, STEFAN (713) 745-4613 MATTIUZZI, GLORIA N. (713) 745-2723 FERRAJOLI, ALESSANDRA (713) 792-2063 NGUYEN, KHANH (713) 563-0295 FREIREICH, EMIL (713) 792-2660 O’BRIEN, SUSAN (713) 792-7543 GARCIA-MANERO, GUILLERMO (713) 745-3428 QUINTAS-CARDAMA, ALFONSO (713) 792-0077 GUSHIKEN, FRANCISCA (713) 745-5789 RAVANDI, FARHAD (713) 745-0394 ILIESCU, GLORIA (713) 563-0502 RYTTING, MICHAEL (713) 792-4855 ISSA, JEAN-PIERRE (713) 745-2260 THOMAS, DEBORAH (713) 745-4616 JABBOUR, ELIAS (713) 792-4764 VERSTOVSEK, SRDAN (713) 745-3429 KADIA, TAPAN (713) 563-3534 WIERDA, WILLIAM (713) 745-0428

Leukemia Insights and other valuable information are now available via the World Wide Web. Our address is: http://www.mdanderson.org/leukemia or you may E-mail us at: [email protected] Editor: Hagop Kantarjian, M.D. WebMaster: Charles A. Koller, M.D. Associate Editor: Sherry Pierce, R.N. Assistant Editor: Jeffrey Sarmiento For referrals, please call 1-877-MDA-6789

9 CLL Treatment Priorities • + Aza (2007-0685) 1. Untreated • AZD1152 vs low-dose Ara-C (2009-0217) • + Cytoxan + Rituximab (FCR) • Vidaza + Revlimid (2009-0467) (2008-0431) • Alternating DAC + (2009-1002) • Lenalidomide + Rituximab (2008-0385) • Sapacitabine (2009-1002) • vs Conventional Care 2. Prior Therapy (2009-1001) • Sorafenib + Azacitidine (2010-0511) • Fludarabine + Cytoxan + Rituximab (ID99-338) • FBR (2009-0546) 2. Salvage Programs • 8-Chloro-adenosine (2004-0144) • (2007-0512) in APL • AMD 3100 (2008-0725) • Fludarabine + Ara-C +Mylotarg (2009-0781) • ABT-263 + FCR or BR (2009-0077) • Lenalidomide (2006-0293) • Lenalidomide + Ofatumumab (2009-0283) • Azacitidine (2007-0405) • Revlimid (2007-0213) • Sapacitabine (2007-0727) • Bafetinib (2010-0175) • Plerixafor + Sorafenib (2008-0501) • PCI-32765 (2010-0314) • DT388IL3 (2008-0313) • SAR103168 (2009-0196) 3. Other • (2009-0434) • Hairy Cell: 2CDA + Rituximab • Vidaza + Revlimid (2009-0467) (2004-0223) • AC220 (2009-0560) • Plerixafor + (2009-0536) • Oral Panobinostat + Vidaza (2009-0619) AML/MDS Treatment Priorities • PR104 (2009-0772) 1. Newly Diagnosed • MK-2206 (2010-0243) A. Acute Promyelocytic Leukemia: cytogenetic • SGI-110 (2010-0615) feature: t(15;17): ATRA + • Ara-C +/- Vosaroxin (2010-0692) +/- (2006-0706) • CIA vs FAI (2010-0788) B. Cytogenetic feature: Inv16 or t(8:21): Fludarabine + Ara-C + Idarubicin (2007-0147) 3. Low Risk MDS and CMML with <10% Blasts • Oral Clofarabine (2005-0536/2007-0410) C. Younger Patients: • Lenalidomide (2006-0293/2009-0737) • IA + SAHA (2007-0835) • Azacitidine (2007-0405) • Ida + Ara -C (2006-0813) • Thymoglobulin + Cyclosporin (2005-0115) • Clofarabine + IA (2009-0431) • LBH589 (2007-0713) • Plerixafor + + Ara-C (2009-0503) • ARRY-614 (2009-0129) • BID FA (2009-0781) • DAC +/- Clofarabine (2008-0092) Older Patients: • Oral Decitabine (2009-0286) • Clofarabine + Ara-C + DAC (2007-0039) • Telintra + Revlimid (2009-0965) • Alemtuzumab (2010-0187)

10

• ON 01910 (2010-0209) • 2CDA + Ara-C (DM97-232) (HES only)

ALL Treatment Priorities • AZD1480 (2009-0067) • Masatinib (2008-0275) 1. Newly Diagnosed or Primary Refractory • LY2784544 (2010-0167) (one non-hyper-CVAD induction) • SB939 (2010-0319) A. Modified Hyper CVAD (ID02-230) • Imetelstat (2010-0672) B. Burkitt’s: Hyper CVAD + Rituximab (ID02-229) C. Ph+: Hyper CVAD + Dasatinib (2006- Phase I/II Agents for Hematologic 0478) Malignancies D. Age <31:Augmented BFM (2006-0375) • L-Grb2 Antisense (2003-0578) E. T cell: Hyper CVAD + • SB939 (2007-0848) (2006-0328) • INCB018424 (2007-0925) 2. Salvage Programs • RO5045337 (2007-0408) • Clofarabine + Cytoxan (2005-0552) • DCC-2036 (2008-0732) • MOAD (2008-0267) • AS703026 (2009-0195) • DT2219ARL (2008-0519) • GSK1120212 (2009-0239) • RAD001 + Hyper CVAD (2009-0100) • Nelarabine (2009-0717) • CMC-544 (2009-0872) • + (2009-0752) • Ponatinib (2010-0570) • LY2523355 (2009-0785) • ABT348 (2009-0788) • Thiarabine (2009-1000) CML Treatment Priorities • PF-04449913 (2010-0078) 1. CML Chronic Phase • TG02 (2010-0244) • Dasatinib (2005-0422) • TH-302 (2010-0268) • Nilotinib (2005-0048/2009-0683) • ON01910 (2010-0303) • INCB018424 (2010-0450) 2. CML Blastic Phase • KB004 (2010-0509) • Ara-C + Fludarabine (2009-0781)

3. T315I Mutations or Advanced Phases • AP24534 (2008-0046/2010-0570) • DCC-2036 (2008-0732)

Myeloproliferative Disorders • Pomalidomide (2007-0199)(MF) • Pegasys (DM03-0109) • INCB018424 (2007-0169)

11 The University of Texas MD Anderson Cancer Center Non-Profit Org. 18013603 U.S. Postage 1515 Holcombe Blvd. - 428 PAID Houston, Texas 77030-4009 Houston, TX Permit No. 7052

Leukemia AddressINSIGHTS Service Requested

Funded in part by the Betty Foster Leukemia Fund

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