Chronic Myeloid Leukemia Outlook: The Future of CML Therapy Neil Shah, MD PhD Edward S. AgenoDistinguished Professor in Hematology/Oncology UCSF School of Medicine San Francisco, California
Progression of CML Bcr-Abl HSC CML-BP (myeloid) CMP CLP CML-BP (lymphoid) Additional mutations GMP MEP Additional mutations MEG CML-CP Blast Phase >30% blasts ~2/3 of patients have myeloid blast crisis ~1/3 have lymphoid blast crisis Very poor prognosis G M RBC Platelets T cell Chronic Phase Myeloid hyperplasia 10% 15% blasts Natural history of disease progression, 3-5 years B cell Accelerated Phase >15%, <30% blasts Basophilia New cytogenetic abnormalities in 50% to 80% of patients
Chronic phase CML is characterized by myeloid expansion HSC LT HSC LT HSC ST HSC ST MPP MPP CLP CMP CLP CMP MEP GMP GMP GrP Gr Normal hematopoiesis CML
15-20 percent of chronic phase CML patients do not achieve deep responses HSC LT HSC LT HSC ST HSC ST MPP MPP CLP CMP CLP CMP GMP GMP GrP GrP Gr Gr CML (untreated) CML in morphologic remission, but without cytogenetic remission
Treatment of CML with TKIs commonly results in profound disease burden reduction, but it is believed that diseased stem cells persist in most if not all patients HSC LT HSC LT HSC ST HSC ST MPP MPP CLP CMP CLP CMP GMP MEP GMP GrP Gr CML (untreated) CML in complete cytogenetic remission
Disease Cure Definitions No evidence of disease by any testing method Given limitations of all testing methods (limited sampling), it is not possible to convincingly demonstrate a complete absence of disease Ability to stop treatment and never suffer disease recurrence Depends upon the expected natural lifespan of patients who have CML (can be >50 years in younger patients) It may be decades before we can convincingly state that a CML patient is cured
ENESTnd 5-Year Update Incidence of MR 4.5 : linearly increasing Patients With MR 4.5, % 100 90 80 70 60 50 40 30 20 10 0 Nilotinib 300 mg BID (n = 282) Nilotinib 400 mg BID (n = 281) Imatinib 400 mg QD (n = 283) 6% to 10% By1 Year a 11%, P<.0001 7%, P<.0001 1% By4 Years a 40%, P<.0001 37%, P=.0002 14% to 17% 23% By5 Years a 54%, P<.0001 52%, P<.0001 21% to 23% 0 1 2 3 4 5 6 31% Time Since Randomization, Calendar Years MR 4.5, molecular response 4.5-logs (BCR-ABL IS 0.0032%). a Cumulative response rates reported consider each year to consist of twelve 28-day cycles. 7 Data cutoff: May 22, 2013
Incidence of MR 4.5 : linearly increasing DASISION 4-Year Follow-up Dasatinib 100 mg QD Imatinib 400 mg QD 60 P=0.030 MR 4.5 50 % With MR 4.5 40 30 20 3% 18% 23% 34% 21% 37% 30% 10 9% 12% 0 2% 0 12 24 36 48 60 MR 4.5 = BCR-ABL (IS) 0.0032% IS = International Scale Months 8
PROVOCATIVE ANECDOTAL CASES
Case 1 (continued) October 2001 Initiated imatinib400 mg daily and rapidly achieved a complete hematologic response.
Case 1 (continued) October 2001 Initiated imatinib400 mg daily and rapidly achieved a complete hematologic response. June 2002 Bone marrow biopsy morphologic remission, mildly hypocellular. Cytogenetics: 46,XX[20] (complete cytogenetic response).
Case 1 (continued) October 2001 Initiated imatinib400 mg daily and rapidly achieved a complete hematologic response. June 2002 Bone marrow biopsy morphologic remission, mildly hypocellular. Cytogenetics: 46,XX[20] (complete cytogenetic response). July 2003 Imatinib held due to pregnancy.
Case 1 (continued) October 2001 Initiated imatinib400 mg daily and rapidly achieved a complete hematologic response. June 2002 Bone marrow biopsy morphologic remission, mildly hypocellular. Cytogenetics: 46,XX[20] (complete cytogenetic response). July 2003 Imatinib held due to pregnancy. Early 2004 Delivered a healthy child. Despite lengthy interruption of imatinib, CBC was normal. BCR-ABL transcript was undetectable by quantitative PCR.
Case 1 (continued) October 2001 Initiated imatinib400 mg daily and rapidly achieved a complete hematologic response. June 2002 Bone marrow biopsy morphologic remission, mildly hypocellular. Cytogenetics: 46,XX[20] (complete cytogenetic response). July 2003 Imatinib held due to pregnancy. Early 2004 Delivered a healthy child. Despite lengthy interruption of imatinib, CBC was normal. BCR-ABL transcript was undetectable by quantitative PCR. Remained off TKI therapy.
Case 1 (continued) October 2001 Initiated imatinib400 mg daily and rapidly achieved a complete hematologic response. June 2002 Bone marrow biopsy morphologic remission, mildly hypocellular. Cytogenetics: 46,XX[20] (complete cytogenetic response). July 2003 Imatinib held due to pregnancy. Early 2004 Delivered a healthy child. Despite lengthy interruption of imatinib, CBC was normal. BCR-ABL transcript was undetectable by quantitative PCR. Remained off TKI therapy. Late 2009 Delivered a second healthy child. Remained off TKI therapy.
Case 1 (continued) October 2001 Initiated imatinib400 mg daily and rapidly achieved a complete hematologic response. June 2002 Bone marrow biopsy morphologic remission, mildly hypocellular. Cytogenetics: 46,XX[20] (complete cytogenetic response). July 2003 Imatinib held due to pregnancy. Early 2004 Delivered a healthy child. Despite lengthy interruption of imatinib, CBC was normal. BCR-ABL transcript was undetectable by quantitative PCR. Remained off TKI therapy. Late 2009 Delivered a second healthy child. Remained off TKI therapy. June 2013 CBC remains normal and BCR-ABL quantitative PCR remains undetectable.
Case 2 November 1998 Diagnosed with chronic phase CML. Simultaneously diagnosed with kidney cancer and underwent nephrectomy Summer 1999 Initiated interferon but did not have a complete hematologic response. Discontinued interferon after ~6 months January 2000 Initiated imatinib(phase II study) April 2000 Cytogenetics reveal Ph chromosome in 6 of 20 metaphases July 2000 Achieved complete cytogenetic response. Over the next seven years, PCR revealed a low but detectable BCR-ABL transcript October 2007 Found to have metastatic kidney cancer. Prescribed preoperative bevacizumabbut had difficulty tolerating it in combination with imatinib. Imatinib held temporarily. BCR-ABL transcript level was 0.004.
Follow-up PCRs: Case 2 (continued) 1/08 0.003 Remained off imatinib
Case 2 (continued) Follow-up PCRs: 1/08 0.003 Remained off imatinib 4/08 weakly positive 7/08 weakly positive 10/08 weakly positive 3/09 weakly positive 6/09 weakly positive 10/09 weakly positive 1/10 weakly positive
Case 2 (continued) Follow-up PCRs: 1/08 0.003 Remained off imatinib 4/08 weakly positive 7/08 weakly positive 10/08 weakly positive 3/09 weakly positive 6/09 weakly positive 10/09 weakly positive 1/10 weakly positive 5/10 negative 8/10 weakly positive 12/10 negative 3/11 weakly positive 6/11 negative 9/11 negative 1/12 negative 4/12 negative 7/12 negative 10/12 negative 1/13 negative 8/13 negative
Patients who maintain CMR of imatinib commonly have evidence of BCR-ABL when assessed with a more sensitive genomic DNA based test Ten patients with loss of CMR had rising gdna PCR levels, whereas gdna was detectable in 7/8 patients with sustained CMR (follow-up 12-41 months) and PCR levels were stable
CML patients treated with dasatinib frequently have clonal T/NK-cell expansion which may be associated with improved response rates and a distinct toxicity profile Ten patients with loss of CMR had rising gdnapcr levels, whereas gdna was detectable in 7/8 patients with sustained CMR (follow-up 12-41 months) and PCR levels were stable
Ph+ ALL patients treated with dasatinib who develop lymphocytosis may have better long-term outcomes
Case 2 (continued) Follow-up PCRs: 1/08 0.003 Remained off imatinib 4/08 weakly positive 7/08 weakly positive 10/08 weakly positive 3/09 weakly positive 6/09 weakly positive 10/09 weakly positive 1/10 weakly positive 5/10 negative 8/10 weakly positive 12/10 negative 3/11 weakly positive 6/11 negative 9/11 negative 1/12 negative 4/12 negative 7/12 negative 10/12 negative 1/13 negative 8/13 negative Lymphocytosis first developed in December 2008. In August 2010, flow cytometric studies revealed a T/NK population; no evidence of CLL
Case 2 (continued) How can this patient s molecular response be explained? Possible explanations include: PCR is detecting a long-lived terminally-differentiated BCR-ABL+ population (e.g. memory B-or T-cells), and not CML stem cells. Stem cells in this case may have been eradicated. CML stem cells are held in check by the immune system. Is the T/NK proliferation evidence of immune activation? Could imatinib negatively impact immune surveillance? Could his brief treatment with interferon in 1999 be responsible? Since a 4.5 log reduction is an arbitrary threshold, is it possible that a substantial proportion of patients with lesser degrees of molecular remission (e.g. stable 3-log reduction) can stop TKI therapy and have prolonged treatment-free remissions?
CML STEM CELLS Can they be eradicated?
A Hedgehog pathway inhibitor (Smo) in conjunction with a BCR-ABL inhibitor suppresses CML stem cells in vitro (LTC-IC assays) Dierks C et al, Cancer Cell 14:238-249
Mechanisms of Leukemic Stem Cell Resistance Stem Cell Niche Quiescence Self Renewal HSC Progenitors T Cells B Cells NK Cells Granulocytes Monocytes TGFbeta Inhibitor Arsenic trioxide FOXO PML Wnt Hedgehog SMO Inhibitor Erythrocytes Platelets Plerixafor JAK Inhibitor Chemokines Cytokines Zileuton Alox5 FTY720 PP2A Acetylation Rac GTPases LSC Autophagy inhibitors HDAC Inhibitors Bcr-Abl TKI T Cells B Cells NK Cells Granulocytes Monocytes Erythrocytes Platelets Chronic Phase CML
CML Stem Cell Eradication Strategies A number of self-renewal pathways have been implicated as critically important in CML stem cells in vitro, and strategies to exploit this information clinically are ongoing TKIs + interferon Smo inhibitors (dasatinib or bosutinib with PF-04449913, dasatinib plus BMS- 833923) Autophagy inhibitors (hydroxychloroquine) Imatinib with or without hydroxychloroquine in newly diagnosed CML patients HDAC inhibitors (imatinib with panobinostat) PML inhibitors (AsO3) with BCR-ABL TKIs 5-LO inhibitors (Zileuton with imatinib) BCR-ABL protein stability inhibitors (HSP90 inhibitors) JAK inhibitors (ruxolitinib) TGF-beta/FOXO inhibitors Activation of p53 by inhibiting SIRT1 TNF-alpha inhibitors Preventing quiescence by targeting FBXW7
CML Stem Cell Eradication Strategies: Challenges Given the possibility that CML stem cells may be very similar to normal stem cells, could all of these pathways truly be critical for the survival of stem cells of CML patients? How to prioritize amongst these many options? Clinical proof-of-concept will require many years of follow-up (complete molecular remission may be an early indicator). In light of the current expected outlook of CML patients with TKI therapy, therapeutic strategies to eradicate CML stem cells must be safe and ideally well-tolerated -in the absence of known activity, even moderate toxicities are difficult to justify
CML Stem Cells: Concluding Thoughts Molecular responses in TKI-treated patients deepen over time, suggesting a gradual elimination of long-lived CML cells that may or may not represent CML stem cells. The ability of some patients to discontinue treatment without evidence of relapse for ten years suggests that some patients may be cured with TKI therapy. While a number of potential interventions to hasten CML stem cell elimination have been identified, the pathway to proof-ofconcept is complicated, and it will likely be years if not decades before definitive proof can be obtained Immunotherapeutic approaches (chimeric antigen receptor T- cells) are demonstrating substantial activity in lymphoid malignancies. Whether myeloid leukemiascan be safely targeted is not clear.