ASH 2012: CML Abstracts

Cortes, MD3, Hagop M. Kantarjian, MD4*, Neil Shah, MD, PhD5, Dale Bixby, MD, PhD6*, Michael J. Mauro, MD7, Ian W. Flinn, MD, PhD8, Thomas O'Hare, PhD1,9, Simin Hu, PhD10*, David J. Dorer10*, Victor M. Rivera, PhD10*, Tim Clackson, PhD10, Christopher D. Turner, MD, FAAP10, Frank G Haluska, MD, PhD10, Brian J. Druker7 and Moshe Talpaz, MD6


Background: Tyrosine kinase inhibitors (TKIs) are the mainstay of therapy for patients (pts) diagnosed with Philadelphia chromosome-positive (Ph+) leukemia. Failure of therapy may occur as a result of intolerance or resistance. Ponatinib is a potent oral pan-BCR-ABL inhibitor that is active against native BCR-ABL, as well as mutated forms of the protein, including the uniformly refractory T315I mutant.

Conclusion: Ponatinib induced high response rates in heavily pretreated pts with resistant or refractory CP-CML (including those with the T315I mutation); responses to ponatinib were durable. Ponatinib was generally well tolerated, and no new safety findings have emerged during long-term follow-up. Updated data will be presented.

https://ash.confex.com/ash/2012/webprogram/Paper46810.html

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Paper49543

915 Efficacy and Safety of Ponatinib in Patients with Accelerated Phase or Blast Phase Chronic Myeloid Leukemia (AP-CML or BP-CML) or Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL): 12-Month Follow-up of the PACE Trial

Hagop M. Kantarjian, MD1*, Dong-Wook Kim2, Javier Pinilla-Ibarz, MD, PhD3*, Philipp le Coutre, MD4, Ronald Paquette, MD, PhD5*, Charles Chuah, MD6*, Franck E. Nicolini, MD, PhD7, Jane Apperley8, H. Jean Khoury, MD9, Moshe Talpaz, MD10, John F. DiPersio, MD, PhD11, Daniel DeAngelo, MD12*, Elisabetta Abruzzese, MD, PhD13*, Delphine Rea, MD, PhD14*, Michele Baccarani, MD15, Martin C Muller, MD16*, Carlo Gambacorti-Passerini, MD17, Stephane Wong, PhD18, Stephanie Lustgarten19*, Victor M. Rivera, PhD19, Tim Clackson, PhD19, Christopher D. Turner, MD, FAAP19, Frank G Haluska, MD, PhD19, Francois Guilhot20, Michael W. Deininger, MD, PhD21, Andreas Hochhaus, MD22, Timothy P. Hughes, MD, MBBS23, John Goldman, DM, FRCP, FRCPath, FMedSci24*, Neil Shah, MD, PhD25, Jorge E. Cortes, MD26 and The PACE Study Group27*

Background: Many patients (pts) with advanced Ph+ leukemias experience failure of all currently available tyrosine kinase inhibitors (TKIs) targeting BCR-ABL and have limited treatment options. Ponatinib is a potent pan-BCR-ABL inhibitor that is active against native and mutated forms of BCR-ABL, including the TKI resistant T315I mutant. The efficacy and safety of ponatinib (45 mg orally once daily) in pts with AP-CML, BP-CML, or Ph+ ALL were evaluated in a phase 2, international, open-label clinical trial.

Conclusions: Ponatinib was generally well-tolerated and had substantial activity in pts with AP-CML, BP-CML, or Ph+ ALL, regardless of mutation status or prior therapy. Data with a minimum follow-up of 12 mos will be presented.


https://ash.confex.com/ash/2012/webprogram/Paper49543.html

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Paper52793

3777 Clarithromycin Enhances tyrosine Kinase Inhibitor – Induced Cell Death by Inhibition of Late Stage Autophagy in Patients with Chronic Myeloid Leukemia At Diagnosis or with Resistant Stage of Disease

A. M. Carella, MD1, G. Beltrami, MD2*, G. Pica, MD2*, C. Ghiggi, MD2*, D. Lovera, MD3*, G. Cirmena4* and A. Garuti4*.
1Department of Hematology and Oncology, IRCCS Azienda Ospedaliera Universitaria S.Martino-IST, Genova, Italy


Background: Recent laboratory studies have demonstrated that clarithromycin (CAM) is effective at increasing the sensitivity of chronic myeloid leukemia (CML) cells to tyrosine kinase inhibitors (TKIs). The mechanism of induction of cell death by CAM combined with TKI appears to be via inhibition of late stage autophagy inhibitor chloroquine ......we treated 8 CML patients. Four consecutive patients, with advanced CML, who were in all cases resistant to TKI alone, achieved remarkable responses to the combination of TKI and CAM (Table 1).
According to this positive experience, we thought that the combination CAM + TKI could be employed upfront at diagnosis, in the attempt to increase a faster complete molecular remission. Until now we have treated four patients at diagnosis...... remarkable responses obtained in these patients support the hypothesis that inhibition of autophagy may make CML cells sensitive to killing by TKIs.

https://ash.confex.com/ash/2012/webprogram/Paper52793.html

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Paper50675

68 Can the Combination of the Measurement of BCR-ABL1 Transcript Levels At 3 and 6 Months Improve the Prognostic Value of the 3 Month Measurement?

Pratap Neelakantan, MRCP1*, Gareth Gerrard, PhD1*, Letizia Foroni1, Dragana Milojkovic1*, Jane Apperley1, Richard Szydlo, PhD2*, Marco Bua1*, Alistair G Reid, BSc, PhD1*, Katy Rezvani, MBBS, PhD, MRCP, FRCPath1, John M Goldman, MD1 and David Marin1.
1Department of Haematology, Imperial College, London, United Kingdom
2Division of Haematology, Imperial College London, London, United Kingdom.

Several groups have shown that that the BCR-ABL1 transcript level measured at 3 or 6 months after starting TKI therapy strongly predicts for the achievement of cytogenetic and molecular responses and for PFS and OS. In particular, we have shown that CML patients treated with imatinib who at 3 months have a transcript level lower than 9.8% on the international scale or lower than 1.67% at 6 months fare significantly better.
We have also shown that the molecular assessment made at 3 months on imatinib therapy is a better predictor of the prognosis of patients than the analysis of BCR-ABL1 transcripts at 6 months. Here we investigate whether it is possible to improve the prognostic accuracy of early measurement of the transcript level by combining the 3 and 6 month results.


https://ash.confex.com/ash/2012/webprogram/Paper50675.html

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Paper52999

916 Discontinuation of Second Generation (2G) Tyrosine Kinase Inhibitors (TKI) in Chronic Phase (CP)-Chronic Myeloid Leukemia (CML) Patients with Stable Undetectable BCR-ABL Transcripts


Delphine Rea, MD, PhD1*, Philippe Rousselot, MD, PhD2*, François Guilhot, MD3, Michel Tulliez, MD4*, Franck E. Nicolini, MD, PhD5, Agnès Guerci-Bresler, MD6*, Laurence Legros, MD, PhD7*, Martine Gardembas, MD8*, Stephane Giraudier, MD, PhD9*, Gaelle Guillerm, MD10* and Francois-Xavier Mahon, MD, PhD11*

Background: TKI have proven remarkably successful against CML. Despite this progress, current recommendation is to never stop therapy. However, prospective trials such as STIM and CML8 suggest that imatinib may be stopped in patients with deep and sustained molecular responses (Mahon et al, Lancet Oncol. 2010; Ross et al, Haematologica 2012). Here, we report on the feasibility of 2G-TKI discontinuation.

Conclusions: 2G-TKI may be safely discontinued in CP-CML patients with long-lasting undetectable BCR-ABL under strict molecular monitoring conditions, especially in patients with prior imatinib intolerance or treated with 2G-TKI as first line therapy. In patients with prior imatinib suboptimal response/resistance, strategies to improve outcome are needed. The recurrence of a low level of detectable residual disease below the MMR threshold after 2G-TKI withdrawal may not automatically herald CML relapse and may not preclude the possibility to remain treatment-free.

https://ash.confex.com/ash/2012/webprogram/Paper52999.html

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Paper54821,br>
72 The Clinical Impact of Time to Response in De Novo Accelerated Phase Chronic Myeloid Leukemia (CML-AP)


Maro Ohanian, DO1*, Hagop M. Kantarjian, MD2, Alfonso Quintas-Cardama, MD2*, Elias J. Jabbour, MD3, Srdan Verstovsek, MD, PhD2, Gautam Borthakur4, Farhad Ravandi, MD2, Guillermo Garcia-Manero, MD2*, Alessandra Ferrajoli2, Tapan M. Kadia, M.D.5, Susan O'Brien, M.D.6 and Jorge E. Cortes, MD7.
University of Texas M.D. Anderson Cancer Center, Houston, TX


Background:
Early (3-month) response is important in chronic phase chronic myeloid leukemia (CML-CP). Whether this applies also to CML in accelerated phase (CML-AP) has not been analyzed.

Conclusion: Pts with de novo CML-AP have an excellent outcome with TKIs, particularly 2GTKIs. As for chronic phase, pts with deep responses at 3 months (MCyR or BCR-ABL <10%) have the best probability of a favorable long-term outcome, although a few have not achieved MCyR at 3 months. TKIs should be standard for all pts with AP features at the time of diagnosis.


https://ash.confex.com/ash/2012/webprogram/Paper54821.html

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Paper54159

3785 Bosutinib As Therapy for Chronic Phase Chronic Myeloid Leukemia Following Failure with Imatinib Plus Dasatinib and/or Nilotinib: 24-Month Minimum Follow-up Update


H. Jean Khoury, MD1, Carlo Gambacorti-Passerini2, Hagop M. Kantarjian, MD3, Dong-Wook Kim4, David Marin5, Pedro E Dorlhiac-Llacer6*, Andrey Zaritskey7,8*, Juan Navarro9*, Eduardo O Bullorsky10*, Sarit Assouline11, Eric Leip12*, Virginia Kelly12, Kathleen Turnbull12*, Nadine Besson13* and Jorge E Cortes, MD14

Bosutinib (BOS) is an orally active, dual Src/Abl tyrosine kinase inhibitor (TKI). This open-label, phase 1/2 study evaluated BOS in patients (pts) with chronic phase chronic myeloid leukemia (CP CML) following TKI failure.

In conclusion, BOS therapy continues to demonstrate durable efficacy and manageable toxicity after follow-up of ³24 mo in CP CML following resistance or intolerance to multiple TKIs, with a majority of pts maintaining response at 2 y and few new transformations, deaths, TEAEs, or discontinuations due to AEs since the prior report ~1 y earlier (Blood 2012;119:4303-12).


https://ash.confex.com/ash/2012/webprogram/Paper54159.html

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Paper53593

2796 Comparison of Disease Outcomes for Patients with Chronic Myelogenous Leukemia in Chronic Phase Switched to Nilotinib or Dasatinib As Second-Line Therapy


James D. Griffin, MD1, Annie Guerin, MSc2*, Lei Chen, MD, PhD3*, Alexander R. Macalalad, MD2*, Jiayuan Luo, MSc2* and Eric Qiong Wu, PhD2

1Dana-Farber Cancer Institute, Boston, MA,2Consulting, Analysis Group, Inc., Boston, MA,
3Novartis Pharmaceuticals Corporation, East Hanover, NJ

Background: Nilotinib and dasatinib are two tyrosine kinase inhibitors (TKIs) commonly used for the treatment of patients with chronic myelogenous leukemia in chronic phase (CML-CP) who are resistant or intolerant to imatinib. Both TKIs have been shown to be more potent than imatinib. However, no head-to-head clinical trials have been conducted comparing the efficacy of nilotinib to dasatinib as 2nd-line therapy for CML-CP patients resistant or intolerant to imatinib. This study compared disease outcomes of patients treated in the community who were switched from imatinib to 2nd-line nilotinib or dasatinib.


ash.confex.com/ash/2012/webprogram/Paper53593.html

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Paper48633

167 Outcome of Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Based On Early Molecular Response and Factors Associated with Early Response: 4-Year Follow-up Data From Enestnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials Newly Diagnosed Patients)


Andreas Hochhaus, MD1, Timothy P. Hughes, MD, MBBS2, Giuseppe Saglio3, François Guilhot4, Haifa Kathrin Al-Ali, MD5*, Giantonio Rosti6, Chiaki Nakaseko, MD, PhD7, Carmino Antonio De Souza, PhD8, Charisse Kemp9*, Xiaolin Fan, PhD10*, Albert Hoenekopp, MD11*, Richard A. Larson, MD12 and Hagop M. Kantarjian, MD13


Background: In the ENESTnd study, nilotinib significantly reduced progression to accelerated phase/blast crisis (AP/BC) and demonstrated superior rates of deep molecular response vs imatinib. Data from ENESTnd demonstrated that significantly more patients achieved early molecular response of both < 10% and < 1% BCR-ABL IS at both 3 and 6 months on nilotinib vs imatinib. Here, we report landmark analyses based on BCR-ABL transcript levels at 3 and 6 months using data with a minimum follow-up of 3 years and also provide data on factors associated with poor early molecular response; data based on longer follow-up of 4 years will be presented.


ash.confex.com/ash/2012/webprogram/Paper48633.html

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Paper53796

70 Early Molecular and Cytogenetic Responses Predicts for Significantly Longer Event Free Survival (EFS) and Overall Survival (OS) in Patients (pts) with Newly Diagnosed Chronic Myeloid Leukemia (CML) in Chronic Phase (CP) – an Analysis of 4 Tyrosine Kinase Inhibitor (TKI) Modalities (standard dose imatinib, high dose imatinib, dasatinib and nilotinib)


Preetesh Jain, MD, DM, PhD1*, Hagop M. Kantarjian, MD1*, Aziz Nazha1*, Elias Jabbour2*, Alfonso Quintás-Cardama, MD3*, Ohad Benjamini, MD1*, Sherry A. Pierce, RN, BS4*, Marylou Cardenas-Turanzas5*, Srdan Verstovsek, MD, PhD1, Gautam Borthakur, M.D.1,6, Farhad Ravandi, MD1, Susan O'Brien, M.D.7 and Jorge E. Cortes, MD1


Introduction: Early responses to TKI are an important predictor of long term outcome. Several approaches have been used to improve outcomes in CML-CP, including high-dose imatinib, and 2ndgeneration TKI. These induce earlier responses and improved long-term outcomes. We analyzed patterns of response and their long-term impact among pts treated with 4 TKI modalities as frontline CML CP therapy.


ash.confex.com/ash/2012/webprogram/Paper53796.html

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Paper49582

694 Switching to Nilotinib Is Associated with Continued Deeper Molecular Responses in CML-CP Patients with Minimal Residual Disease After ≥ 2 Years On Imatinib: Enestcmr 2-Year Follow-up Results


Timothy P. Hughes, MD, MBBS1, Jeffrey H. Lipton, MD, PhD2, Nelson Spector, MD, PhD3, Brian Leber, MD4, Ricardo Pasquini, MD, PhD5, Nelma Clementino, MD6*, Anthony P. Schwarer, MD7, Gabriel Etienne, MD, PhD8*, Agnès Guerci-Bresler, MD9*, Susan Branford, PhD10, Das Purkayastha11*, LaTonya Collins, BSN12*, Tomasz Szczudlo13 and Francisco Cervantes, MD, PhD14

Background: Superior rates of deeper molecular responses were achieved with nilotinib vs imatinib in patients newly diagnosed with Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP) in the Evaluating Nilotinib Efficacy and Safety in Clinical Trials—newly diagnosed patients (ENESTnd) trial. In addition, the 12-month (mo) analysis of the ENEST—complete molecular response (ENESTcmr) study demonstrated that switching to nilotinib after a minimum of 2 years on imatinib led to increased rates of major molecular response (MMR) and deeper molecular responses vs remaining on imatinib. Results from ENESTcmr are presented here with minimum 24 mo of patient follow-up.


ash.confex.com/ash/2012/webprogram/Paper49582.htm

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Abstract:3784

5yr Results of Nilotinib 400 mg BID in early CP CML : Update of the Gimema CML WP Trial CML0307

Conclusions:
After a median follow-up of 5 years, the great majority of patients are still on nilotinib and, reasonably, they will continue in the next future. Even more importantly, only 1 progression so far: considering the kinetic of progression with any TKI in CML (most progressions reported during the first 2-3 years with imatinib and during the first 1-2 years with nilotinib and dasatinib), a relevant future progression incidence is very unlikely. Given the very high rate of deep molecular response, many are candidate to treatment discontinuation.


ash/2012/webprogram/Paper54145.html

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Abstract: 3777

Clarithromycin Enhances tyrosine Kinase Inhibitor – Induced Cell Death by Inhibition of Late Stage Autophagy in Patients with Chronic Myeloid Leukemia At Diagnosis or with Resistant Stage of Disease

Recent laboratory studies have demonstrated that clarithromycin (CAM) is effective at increasing the sensitivity of chronic myeloid leukemia (CML) cells to tyrosine kinase inhibitors (TKIs). The mechanism of induction of cell death by CAM combined with TKI appears to be via inhibition of late stage autophagy inhibitor chloroquine. This is clearly demonstrated by an increase in LC3-II protein levels and a concomitant increase in cellular vacuole formation (L. Shafranek, T.P. Hughes, Leukemia & Lymphoma 2012, early online 1-4). On our protocol, approved by our Ethical Committee, we treated 8 CML patients. Four consecutive patients, with advanced CML, who were in all cases resistant to TKI alone, achieved remarkable responses to the combination of TKI and CAM (Table 1). According to this positive experience, we thought that the combination CAM + TKI could be employed upfront at diagnosis, in the attempt to increase a faster complete molecular remission......

Three out four patients treated at diagnosis achieved CCyR and MMR at 3, 3, 6 months and 5, 10 and 12 months, respectively. No patient has gone off study for toxicity and in no case we observed grade 3-4 myelosuppression. The remarkable responses obtained in these patients support the hypothesis that inhibition of autophagy may make CML cells sensitive to killing by TKIs.


ash/2012/webprogram/Paper52793.html

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Abstract 3768

Switching to a Second Generation TKI in Chronic Myeloid Leukemia Patients with Late Suboptimal Response with Imatinib Obtained Better Molecular Responses That the “Watch and Wait” Approach. an Experience of a Multicenter Registry in Patients Outside Clinical Trials

Results: The use of 2G TKIs resulted in significant benefit to patients in terms of improving molecular responses. Complete molecular responses (CMR) and MMR rates were 3.8% vs 27% and 41.5% vs 69% for group 1 and 2 respectively (p=0.006). Time for the achievements the best molecular responses was significantly lower for patients receiving second generation TKI (4.1 vs 20.2 months, p=0.004). Probabilities of treatment failure, defined as loss of CCR, were also higher in patients remaining with imatinib (15.4% vs 5.7% (p=0.12). Progression free survival was 93.8% vs 97.2% (p=0.18) for group 1 and 2 respectively. Changing treatment for late SubR patients was also safe, and only 17% of patients needed to switch to another TKI due to intolerance.


Conclusions: In CML patients treated with Imatinib with late SubR, and outside clinical trials, switching to second generation TKI increased probabilities of achievement a deeper molecular response, with a good safety profile.


ash/2012/webprogram/Paper52088.html

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Paper48739
Early Molecular Response and Female Sex Strongly Predict Achievement of Stable Undetectable BCR-ABL1, a Criterion for Imatinib Discontinuation in Patients with CML


Susan Branford, PhD1, David Ross, MBBS, PhD2*, Jodi Prime, BSc.3*, Chani Field, BSc4*, Haley Altamura, BSc4*, Alexandra Yeoman, BSc4*, Jasmina Georgievski, BSc4*, Stuart Phillis, BSc4*, Bronte A Jamison, BSc5*, Brad Sullivan, BSc4*, David T Yeung, BSc, MBBS, FRACP, FRCPA6 and Timothy Hughes, MD, MBBS7


Introduction.

The opportunity to discontinue kinase inhibitor therapy while maintaining a deep remission is desirable for many CML patients. Despite good responses to imatinib for most patients, treatment related side effects remain problematic and can affect quality of life. Studies have demonstrated that a proportion of carefully selected patients can sustain response after imatinib discontinuation. The first requirement for successful discontinuation is likely to be stable deep molecular response based on a sensitive RQ-PCR assay.

The criteria for patient selection in the French Stop Imatinib (STIM) and Australian CML8 (TWISTER) imatinib discontinuation trials included stable undetectable BCR-ABL1 transcripts for at least 24 months with a PCR sensitivity of 5 and 4.5 log, respectively. The probability of continued remission after discontinuation for imatinib treated patients without prior interferon-α therapy was approximately 33%. It is not known how many imatinib treated patients will eventually meet these PCR criteria for a discontinuation trial.

https://ash.confex.com/ash/2012/webprogram/Paper48739.html

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Paper47254

3745 Activation Levels of Natural Killer Cells and CD8+ T Cells Correlate Highly with Sustained Complete Molecular Response After Discontinuation of Imatinib in Chronic Myeloid Leukemia Patients


Seiichiro Katagiri, MD1*, Izuru Mizoguchi, PhD2*, Takayuki Yoshimoto, PhD2*, Junichiro Mizuguchi, MD, PhD3*, Junko H Ohyashiki, MD, PhD4* and Kazuma Ohyashiki, MD, PhD1


Introduction: Recently, it has been recognized that some chronic myeloid leukemia (CML) patients with a complete molecular response (CMR) are able to maintain the CMR after discontinuation of imatinib. Mahon et al. reported that among patients with a CMR lasting at least 2 years, CMR was sustained in 41% after discontinuation of imatinib (Lancet Oncol. 2010;11:1029). Similarly, Takahashi et al. reported that 47% of Japanese CML patients with CMR maintained CMR after imatinib discontinuation (Haematologica 2012;97:903). Moreover, Ohyashiki et al. have recently demonstrated that higher peripheral natural killer (NK) cell counts are associated with a reduced risk of relapse after halting imatinib (Br. J. Haematol. 2012;157:254). These findings suggest that, although CML stem cells may remain, even if CMR status is attained, some CML patients could discontinue imatinib therapy and maintain a stable condition, possibly owing to immune surveillance.


https://ash.confex.com/ash/2012/webprogram/Paper47254.html