‘Can we eventually stop TKI in all CML patients?’ John Goldman Controversies in Hematology Rome, 12 September 2010
Evidence and concepts in favour of the notion that TKI rarely eliminates residual leukemia cells The vast majority of responding patients relapse within a few weeks or months if they discontinue treatment with imatinib or a 2G-TKI In vitro studies show that ‘quiescent’ stem cells are resistant to both imatinib and dasatinib Complete molecular response is consistent with survival of up to 10 7 leukemia cells; a DNA based PCR may be more sensitive than conventional cDNA-based PCR The analogy with results of allogeneic stem cell transplantation support the concept that small numbers of leukemia stem cells may remain in the body for many years and then regenerate leukemia
Targeting quiescent stem cells LSC may be entirely eradicated by continued treatment with imatinib or 2G-TKI If they are not, there are three situations where quiescent LSC may remain innocuous: 1. They are inhibited or undergo apoptosis in the presence of TKI as soon as they start to cycle, 2. Progression to advanced phase occurs always at the level of a more committed progenitor cell, or 3. Low levels of LSC are readily controlled by immunological mechanisms that don’t work with large cell numbers
If eliminating residual disease really is important, what can we do to target them effectively? Use existing TKIs according to different schedules Use TKIs in combination with new anti-BCR-ABL drugs. Use TKIs in conjunction with signal transduction inhibitors or epigenetic inhibitors – eg FTIs, HDAC inhibitors, autophagy inhibitors, PP2A activators and others Immunotherapy with vaccines or CTLs directed against BCR-ABL, WT1, PR3, PRAME, etc
Eliminating residual leukaemia cells 1. Does elimination of more differentiated progenitor cells (eg GMP) prevent leukaemia progression? 2. Does adherence become more of a problem as patients continue therapy for some years? 3. Do we need develop more sensitive techniques for measuring residual disease in general and for leukaemia ‘stem cells’ in particular? 4. If eliminating residual disease really is important, what can we do to target them effectively ?
Does elimination of more differentiated progenitor cells (eg GMP) prevent leukaemia progression?
β -catenin and leukaemic stem cell self-renewal - β -catenin is activated by Wnt and Frizzled; loss of β -catenin impairs CML LSC renewal (Zhao, Reya et al, 2007) - β -catenin is normally inactivated in the cytoplasm by APC/GSK3 β /axin complex - When activated β -catenin enters the nucleus and combines with LEF and TCF and induces excessive self-renewal by targeting expression of cyclin D1 and MYC -Mis-splicing of exons 8 and 9 of the GSK-3 β gene could contribute to survival of β -catenin in blastic phase - PKF-115 interferes with the β -catenin /LEF/TCF complex and reverses excessive stem cell renewal in a mouse xenograft model
In myeloid blastic crisis β -catenin is over-expressed in GMP compared with putative stem cells Jamieson et al. N Engl J Med. 2004;351:657-667.
β -catenin and leukaemic stem cell self-renewal - β -catenin is activated by Wnt and Frizzled; loss of b-catenin impairs CML LSC renewal (Zhao, Reya et al, 2007) - Normal β -catenin is normally inactivated in the cytoplasm by APC/GSK3 β /axin complex - When β -catenin enters the nucleus it combines with LEF and TCF and induces excessive self- renewal by targeting expression of cyclin D1 and MYC - Mis-splicing of exons 8 and 9 of the GSK-3 β gene could contribute to survival of β -catenin in blastic phase - PKF-115 interferes with the β -catenin/ LEF/TCF complex and reverses excessive stem cell renewal in a mouse xenograft model
Actual target for myeloblastic progression LT-HST ST-HST MPP CD33 CLP CMP CD123 MEP GMP Erythrocytes, Pro-T Pro-NK Pro-B Granulocytes, platelets macrophages T-cells NK-cells B-cells
Loss of p16 in lymphoblastic transformation of CML Chromosome 9 9p21.3 CDKN2A (p16, INK4A) Homozygous deletions of the p16 [CDKN2A] tumor suppressor gene are associated with lymphoid transformation of CML H Sill, JM Goldman and NC Cross. Blood 1995; 85: 2013-2016
Coincidental loss at 7p and 9p in CML in lymphoblastic transformation 7p15.2 7p14.1 7p12.2 HOXA7 TRAP IKZF1 (Ikaros) 9p24.1 9p21.3 9p13.2 PDCD1LG2 PAX5 MLLT3 JMJD2C CDKN2A (p16) Background p16 lost in 50% of patients with CML-BT(L) (Sill et al, 1995) IKZF1 (Ikaros) lost in majority of 20/22 adults and 16/21 children with Ph+ALL, possibly due to aberrant RAG-mediated recombination. CDKN2A (p16) lost in 53% of patients. Inactivating mutations found in PAX5 (Mullighan et al, 2008)
Actual target for lymphoblastic progression LT-HST ST-HST MPP CD10 CD19 CLP CMP MEP GMP Erythrocytes, Pro-T Pro-NK Pro-B Granulocytes, platelets macrophages T-cells NK-cells B-cells
Does elimination of more differentiated progenitor cells (eg GMP) prevent leukaemia progression? The preliminary evidence suggesting that the expanded ‘clone’ myeloid blastic transformation derives from a genetically altered GMP population (at least in some cases) taken together with the phenotypic data could mean that the answer is ‘yes’
Does adherence become more of a problem as patients continue therapy for some years? After some years on imatinib patients a relatively high proportion of patients appear to be taking less than the prescribed dose. This conclusion is based on reasonably objective measurements.
Do we need develop more sensitive techniques for measuring residual disease in general and for leukaemia ‘stem cells’ in particular?
BCR-ABL1 transcript measurement is still not sensitive enough to assess good responders Decreasing residual 1000 13 Leucocytosis leukaemia 100 BCR-ABL1/ABL1 ratio (%) 12 N u Ph-chromosome pos 10 m 11 b 1 10 e r Ph-negative but 0.1 o 9 f RQ-PCR positive l 0.01 e 8 u k 0.001 7 a e 0.0001 m 6 i a ? 5 c e 4 l l s ( 3 l o g 10 2 ) 1 Cure ? 0 0
Patterns of residual disease in IM-treated patients in CMR gDNA+ gDNA+ Sobrinho-Simoes et al, Blood 2010
If eliminating residual disease really is important, what can we do to target them effectively?
If eliminating residual disease really is important, what can we do to target them effectively? Use existing TKIs according to different schedules
If eliminating residual disease really is important, what can we do to target them effectively? Use existing TKIs according to different schedules Use TKIs in combination with new anti-BCR-ABL drugs.
If eliminating residual disease really is important, what can we do to target them effectively? Use existing TKIs according to different schedules Use TKIs in combination with new anti-BCR-ABL drugs. Use TKIs in conjunction with signal transduction inhibitors or epigenetic inhibitors – eg FTIs, HDAC inhibitors, autophagy inhibitors, PP2A activators and others
BMS-214662 inhibits CML LTC-IC colony formation P=0.032 250 P=0.027 CML % No drug contro 200 P=0.033 150 100 50 0 No drug BMS-214662 IM 5uM BMS-214662 Dasatinib BMS-214662 control 250nM + IM 150nM + Dasatinib Condition IM and dasatinib protect CML stem cells and result in increased colony formation (p=0.033 versus no drug control) Virtual elimination of all colonies in the BMS-214662-containing arms Copland et al, Blood 2008; 111: 2843-53
If eliminating residual disease really is important, what can we do to target them effectively? Use existing TKIs according to different schedules Use TKIs in combination with new anti-BCR-ABL drugs. Use TKIs in conjunction with signal transduction inhibitors or epigenetic inhibitors – eg FTIs, HDAC inhibitors, autophagy inhibitors, PP2A activators and others Immunotherapy with vaccines or CTLs directed against BCR-ABL, WT1, PR3, PRAME, etc
The inescapable conclusion is TKI alone suppress the bulk of leukemia cells in responding patients but do ..not eradicate residual stem cells so additional measures are required to cure CML
The inescapable conclusion is TKI alone suppress the bulk of leukemia cells in responding patients but do not eradicate residual stem cells, so additional measures are required to cure CML
The end
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