Targeting BCL-2, BCL-XL, BCL-W and MDM2 in B-Cell Acute Lymphoblastic Leukemia Is Highly Effective Ex Vivo

Abstract Despite the advances in the treatment of acute lymphoblastic leukemia (ALL), a major fraction of adult patients still succumb to leukemia- or treatment-related events. In particular, the outcome of elderly ALL patients remains dismal. Our aim was to discover new or repurposed drugs for B-cell ALL in a clinically relevant ex vivo drug sensitivity testing platform. We analyzed 19 primary B-ALL samples using a well-established drug sensitivity and resistance testing platform and a drug panel including 65 drugs in five different concentrations. The main drug classes were glucocorticoids, MDM2 antagonists, and inhibitors of BCR-ABL1, VEGFR, BCL-2, BCL-XL, BET, MEK, JAK, Aurora kinase, PI3K, MTOR, IGF1R, ERK, STAT3, STAT5, HSP90 and NAMPT proteins. The samples were viably frozen bone marrow (BM) mononuclear cells collected at diagnosis. The cohort included both Philadelphia-positive (Ph+) (n=10) and Ph-negative (Ph-) (n=9) patients with a median age of 43 years (range 22-68). Cell viability (CellTiter-Glo) was measured after plating and after a three-day incubation with the drugs. A drug sensitivity score (DSS) was calculated from the viability readouts, which takes into account the area under the dose response curve, measuring both drug efficacy and potency. DSS values >10 are considered effective and >20 highly effective. As an overall view of drug sensitivity, a heatmap and dendrograms from DSS values are shown in Figure 1A. As expected, most patients were sensitive to glucocorticoids and tyrosine kinase inhibitors (TKIs) showed efficacy in Ph+ ALL. In addition, two Ph-negative patients were sensitive to TKIs, suggesting a Philadelphia-like disease. Drugs that showed pan-ALL efficacy included BCL-2 family inhibitors, idasanutlin (MDM2 inhibitor), luminespib (HSP90 inhibitor), daporinad (NMPRT inhibitor) and plicamycin (antineoplastic antibiotic). For the other drugs, only individual patients showed sensitivity, in line with the diverse molecular background of ALL. Strikingly, 17/19 (89%) of patients in our cohort were highly sensitive (DSS>20) to navitoclax (a BCL-2, BCL-XL and BCL-W inhibitor), whereas the BCL-2-specific inhibitor venetoclax was effective only in a distinct subset of patients (Figure 1B). 6/19 (32%) of patients were highly sensitive (DSS>20) to venetoclax and represented all risk classes based on age, white blood cell counts and karyotype, but interestingly, all were Ph-negative. Overall, response to venetoclax correlated with response to navitoclax (Spearman, r=0.85; P<0.0001). To examine differential gene expression of anti-apoptotic proteins between Ph+ and Ph- patients, we analyzed microarray gene expression data from ArrayExpress public database (www.ebi.ac.uk/arrayexpress, E-MTAB-5035). The analyzed cohort included 96 Ph- and 41 Ph+ adult B-ALL patients. Ph-negative samples were characterized with higher BCL-2 expression, whereas Ph-positive samples showed higher BCL-W expression and a trend to higher BCL-XL expression (Figure 1C). Thus, lack of venetoclax efficacy ex vivo in Ph-positive ALL indicated dependence on BCL-W and BCL-XL, as also reflected in the gene expression analyses. Inhibitors of BCL-2, such as navitoclax and venetoclax, potently induce apoptosis in a variety of cancer cells. Both inhibitors showed promising efficacy in our B-ALL samples. Dose-limiting thrombocytopenia has limited the use of navitoclax in solid tumors. However, in our assay navitoclax showed more uniform potency, particularly in Ph+ samples suggesting a rational combination with tyrosine kinase inhibitors. Similar to conventional cytotoxic agents used in ALL, a therapeutic window may exist for safe use of navitoclax in acute leukemia. In conclusion, targeting the multidomain anti-apoptotic proteins (BCL-2, BCL-XL, BCL-W, MCL-1) and TP53 with MDM2, possibly in combination, is a promising strategy for improving outcome of adult B-ALL. Figure 1. Figure 1. Disclosures Hohtari: Incyte: Research Funding. Heckman:Novartis: Research Funding; Celgene: Research Funding; Orion Pharma: Research Funding. Wennerberg:Novartis: Research Funding. Mustjoki:Ariad: Research Funding; Pfizer: Honoraria, Research Funding; Celgene: Honoraria; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Porkka:Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

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Clinical Relevance of Tyrosine Kinase Fusion Genes in Pediatric BCR-ABL1-like Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood.v126.23.3735.3735 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3735-3735 ◽

Cited By ~ 1

Author(s):

Judith M. Boer ◽

Aurélie Boeree ◽

João R.M. Marchante ◽

Berna Beverloo ◽

Gabriele Escherich ◽

...

Keyword(s):

Gene Expression ◽

Acute Lymphoblastic Leukemia ◽

Tyrosine Kinase ◽

B Cell ◽

Signaling Pathway ◽

Ex Vivo ◽

Lymphoblastic Leukemia ◽

Fusion Genes ◽

Rt Pcr ◽

Cell Precursor

Abstract Background Patients with pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with the BCR-ABL1 fusion gene form a small high-risk patient group with a poor prognosis. Approximately 15% of BCP-ALL are characterized by a gene expression signature similar to that of BCR-ABL1-positive disease and an unfavorable prognosis. This BCR-ABL1-like group shows a high frequency of B-cell development gene aberrations, especially IKZF1 deletions and tyrosine kinase-activating lesions (Den Boer et al. Lancet Oncol 2009; Mullighan et al. N Engl J Med 2009; Roberts et al. Cancer Cell 2012, N Engl J Med 2014; Van der Veer et al. Blood 2013). Aims To evaluate the clinical value of tyrosine kinase fusions in newly diagnosed children with B-cell precursor ALL, we studied their frequency, prognosis and drugability in a Dutch/German cohort. Methods This study comprised 204 children with BCP-ALL in three Dutch trials (DCOG ALL-8, 9, 10) and two German trials (COALL 06-97, 07-03) including 92 previously described BCR-ABL1-like cases identified by hierarchical clustering and 112 non-BCR-ABL1-like B-other cases. Molecular characterization included RT-PCR and FISH to detect fusions involving ABL1, PDGFRB, JAK2 and CSF1R, gene expression analysis, and copy number analysis. Results We identified 12 tyrosine kinase-activating fusion genes among 73 tested BCR-ABL1-like cases (16%) and none among 87 tested B-other cases. Eight fusions activated the ABL signaling pathway: 4 EBF1-PDGFRB, ZMIZ1-ABL1, RCSD1-ABL2, SSBP1-CSF1R, and one case with split ABL1 and an unknown fusion partner. Four fusions activated the JAK signaling pathway: 2 PAX5-JAK2, BCR-JAK2, and TERF2-JAK2. The gene fusions were confirmed by RT-PCR or targeted locus amplification. Gene expression of the involved tyrosine kinase was high in each of the fusion cases. IKZF1 deletions occurred more frequently in tyrosine kinase fusion cases compared with non-BCR-ABL1-like B-other cases (55% vs. 32%; p=0.2), and were enriched for rare, i.e. other than exon 4-7 or full deletion, variants (45% vs. 18%; p=0.05). In the remaining BCR-ABL1-like cases, the frequency of rare IKZF1 variants was similar to that in B-other (17%). Single deletion of exon 16 of EBF1 occurred in the EBF1-PDGFRB fusions and was rare among the remaining BCR-ABL1-like (0/77) and B-other cases (2/105). High CRLF2 expression co-occurred only in the BCR-JAK2 fusion case. The cumulative incidence of relapse (CIR) in the BCR-ABL1-like group with tyrosine kinase fusions (8-yr CIR 40% ± 18%) was comparable with that in the remaining BCR-ABL1-like group (8-yr CIR 36% ± 6%), and worse than in the B-other group (8-yr CIR 19% ± 4%; overall Gray p=0.04). Of the 12 tyrosine kinase fusion cases, four were late responders who only achieved remission after day 33 of induction therapy, and one was a non-responder resulting in early death. This non/late response rate was significantly higher in the tyrosine kinase fusion cases compared with non-BCR-ABL1 -like B-other (42% vs. 9%, p=0.008) and also higher compared with the remaining, fusion-negative BCR-ABL1-like cases (42% vs. 17%, p=0.06). Leukemic cells from three EBF1-PDGFRB patients were sensitive to 15 and 30 µM imatinib in ex vivo cultures, compared with lack of cytotoxic response in four EBF1-PDGFRB-negative samples, two of which even showed growth on imatinib. Combination of imatinib with 100 µg/ml prednisolone resulted in further growth inhibition in 2/3 EBF1-PDGFRB patients' ex vivo cultures. Conclusions Tyrosine kinase fusion genes were found in 16% of DCOG/COALL BCR-ABL1-like cases, representing ~3% of total BCP-ALL. BCR-ABL1-like cases with tyrosine kinase fusions were characterized by poor initial response to treatment, had an unfavorable clinical outcome compared with non-BCR-ABL1-like B-other ALL cases and a similar unfavorable outcome compared with tyrosine kinase fusion-negative BCR-ABL1-like cases. Imatinib worked additive to prednisolone in EBF1-PDGFRB patients' cells, indicating that this inhibitor may be clinically used in combination with at least prednisone. These results are in line with promising results of refractory EBF1-PDGFRB-positive and other ABL class fusion patients successfully treated with imatinib added to consolidation chemotherapy (Lengline et al. Haematologica 2013; Weston et al. J Clin Oncol 2013; Roberts et al. N Engl J Med 2014). Disclosures No relevant conflicts of interest to declare.

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NUP214-ABL1 fusion defines a rare subtype of B-cell precursor acute lymphoblastic leukemia that could benefit from tyrosine kinase inhibitors

Haematologica ◽

10.3324/haematol.2015.136499 ◽

2015 ◽

Vol 101 (4) ◽

pp. e133-e134 ◽

Cited By ~ 16

Author(s):

Nicolas Duployez ◽

Guillaume Grzych ◽

Benoît Ducourneau ◽

Martin Alarcon Fuentes ◽

Nathalie Grardel ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Tyrosine Kinase ◽

B Cell ◽

Tyrosine Kinase Inhibitors ◽

Kinase Inhibitors ◽

Lymphoblastic Leukemia ◽

Cell Precursor

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Treating Ph+ Acute Lymphoblastic Leukemia (ALL) in the Elderly: The Sequence of Two Tyrosine Kinase Inhibitors (TKI) (Nilotinib and Imatinib) Does Not Prevent Mutations and Relapse.

Blood ◽

10.1182/blood.v120.21.2601.2601 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2601-2601 ◽

Cited By ~ 4

Author(s):

Cristina Papayannidis ◽

Paola Fazi ◽

Alfonso Piciocchi ◽

Francesco Di Raimondo ◽

Giovanni Pizzolo ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Tyrosine Kinase ◽

Research Funding ◽

Kinase Inhibitors ◽

Lymphoblastic Leukemia ◽

The Elderly ◽

Kinase Domain ◽

Intensive Chemotherapy ◽

Molecular Responses ◽

Abl Kinase

Abstract Abstract 2601 Background: Tyrosine Kinase Inhibitors (TKI) have been shown to be very effective for the treatment of Acute Lymphoblastic Leukemia (ALL), with a Complete Hematologic Remission (CHR) rate close to 100%, and a high rate of Complete Cytogenetic and Molecular responses (CCgR and CMR). However, when they are used alone, as single agents, most patients relapse, so that they are currently used in combination with chemotherapy and as a preparation to allogeneic stem cell transplantation (SCT). Since Ph+ ALL is more frequent in the elderly, many patients cannot tolerate intensive chemotherapy and are not eligible for SCT. We have explored if the administration of two TKIs, Nilotinib (NIL) and Imatinib (IM) can improve the results without increasing the toxicity. Aims: To evaluate the response and the outcome of Ph+ ALL patients treated with the sequential administration of NIL and IM, to investigate the type and number of BCR-ABL kinase domain mutations developing during and after the study. Methods: We have designed a study (ClinicalTrials.gov. NCT01025505) in which patients more than 60 years old or unfit for intensive chemotherapy and SCT where treated with two TKIs, NIL 400 mg twice daily, and IM 300 mg twice daily, alternating for 6 weeks for a minimum of 24 weeks (study core) and indefinitely in case of response. The 6-weeks rotation schedule was respected, irrespectively of temporary discontinuations. The primary end-point was the rate of Disease Free Survival (DFS) at 24 weeks (4 courses of treatment); the secondary end points included the evaluation of CHR, CCgR and CMR rates. Mutation analysis was performed by nested RT-PCR amplification of the ABL kinase domain of the BCR-ABL transcript (codons 206 through 421). Amplified products were screened by denaturing-high performance liquid chromatography (D-HPLC). Samples scored positive for the presence of sequence variations were then subjected to direct automatic sequencing to characterize the mutation. Results: 39 patients have been enrolled in 15 Italian hematologic Centers (median age 66 years, range 28–84). Among these, 8 patients were unfit for standard chemotherapy or SCT (median age 50 years, range 28–59). 27 patients were p190, 5 were p210 and 7 were p190/p210. After 6 weeks of treatment, 36 patients were evaluable for response: 34 were in CHR (94%) and 2 in PHR (6%). 23 patients have already completed the study core (24 weeks), 87% were in CHR and 17 are currently continuing therapy in the protocol extension phase. Thus, the OS at 1 year is 79%, and 64% at 2 years. Overall, 1 patient was primarily resistant and 13 patients have relapsed, with a median time to relapse of 7.6 months (range 0.8–16.1 months), for a DFS of 51.3% at 12 months (Figure 1). Mutations detected were T315I in 2 cases, Y253H in 3 cases, T315I and Y253H in 1 case, E255K in 1 case, T315I and E255K in 1 case, E255V and Y253H in 1 case. Two patients were WT. A detailed kinetics of Molecular responses is shown in Table 1. Data on mutational analysis are reported in Table 2. Further details about Cytogenetic and Molecular responses, and about Adverse Events will be provided on site. Conclusions: In this small cohort of Ph+ ALL elderly/unfit patients, the rates of relapse and progression were not likely to be different from the rates observed with Imatinib alone (Vignetti et al, Blood 2007, May 1;109(9):3676-8) and Dasatinib alone (Foà, Blood 2011, Dec 15;118(25):6521-8). It's important to notice that the mutations that occurred at the time of relapse were sensitive to other TKIs (Dasatinib and Ponatinib). Acknowledgments: COFIN, Bologna University, BolognAIL, PRIN, Fondazione del Monte di Bologna e Ravenna, INPDAP. Disclosures: Pizzolo: Hoffmann-La Roche: Consultancy, Honoraria. Luppi:CELGENE CORPORATION: Research Funding. Vallisa:CELGENE CORPORATION: Research Funding. Martinelli:NOVARTIS: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; PFIZER: Consultancy; ARIAD: Consultancy. Baccarani:ARIAD, Novartis, Bristol Myers-Squibb, and Pfizer: Consultancy, Honoraria, Speakers Bureau.

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Inotuzumab Ozogamicin (Ino) May Overcome the Impact of Philadelphia Chromosome (Ph)-like Phenotype in Adult Patients (pts) with Relapsed/Refractory (R/R) Acute Lymphoblastic Leukemia (ALL)

Blood ◽

10.1182/blood-2019-126940 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1641-1641 ◽

Cited By ~ 1

Author(s):

Elias Jabbour ◽

Kathryn G. Roberts ◽

Koji Sasaki ◽

Yaqi Zhao ◽

Chunxu Qu ◽

...

Keyword(s):

Gene Expression ◽

Overall Survival ◽

Stem Cell ◽

Acute Lymphoblastic Leukemia ◽

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Lymphoblastic Leukemia ◽

Advisory Committees ◽

The Impact

Background: Ino showed significant activity in phase II trials in pts with R/R ALL, that was subsequently confirmed in Phase III trial where Ino demonstrated higher response rates and superior overall survival vs standard of care chemotherapy (SOC) in adults with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (R/R ALL).Ph-like or BCR-ABL1-like ALL possesses a gene expression profile similar to that of BCR-ABL1 ALL but lacks the BCR-ABL1 fusion protein. It is characterized by increased expression of hematopoietic stem-cell genes, deletion of B-cell lineage genes and kinase-activating alterations. Ph-like ALL is associated with refractoriness to standard induction/consolidation chemotherapy and poor prognosis. Aim: To evaluate the outcomes of pts with R/R Ph-like ALL treated in phase II trial with Ino monotherapy. Methods: We performed an integrated analysis of whole genome sequencing (to identify sequence mutations, structural variations and DNA copy number alterations), and transcriptome sequencing (RNAseq; to quantify gene expression, determine Ph-like gene expression profile and identify fusions) on 53 patients' samples treated with Ino between June 2010 and September 2012. Results: Fifty-three evaluable pts with R/R ALL with stored baseline samples were analyzed. Pts characteristics are summarized in Table 1. Median age was 50 years. Ino was given as Salvage 1, Salvage 2, and Salvage 3 and beyond in 20 (38%), 18 (34%), and 15 (28%) pts, respectively. Figure 1 reflects the different genomic subgroups identified among 53 evaluable pts. Ph-like gene signature was found in 12 pts (22.6%). Among these 12 pts, 6 had IGH-CRLF2, 2 IGH-EPOR, 1 SNX2-ABL1, and 3 had no fusions identified. The overall response rates (ORR) were 54% [complete remission (CR) 20%, CR with partial hematologic recovery (CRh) 32%, and marrow CR (CRi) 2%]. Among pts with morphologic remission, 46% and 82% achieved minimal residual disease (MRD) negativity at CR and at any time, respectively. The ORR for pts with Ph-like ALL, Ph-positive ALL, ALL with KMT2A, and others were 58% (CR=25%; CRh=33%), 42% (CR=8%; CRh=33%), 57% (CR=14%; CRh=29%; CRi=14%), and 56% (CR=26%; CRh=30%), respectively. The respective overall MRD negativity rates were 71%, 100%, 75%, and 83% (Table 1). The median follow-up was 60 months. The median event-free (EFS) and overall survival (OS) were 3.3 and 5.4 months, respectively. There was no difference in EFS and OS between the subgroups analyzed (P=0.464; P=0.824). The median EFS and OS were 4.5 and 4.5 months for pts with Ph-like, 3.1 and 7.2 months for those with Ph-positive ALL, 2.8 and 4.4 months for those with KMT2A, and 2.2 and 4.6 months for others (Table 1). 21 (40%) pts had subsequent allogeneic stem cell transplant; 6 (50%), 3 (25%), 4 (57%), and 8 (36%) in each subgroup, respectively. The rate of VOD was 3 (6%) with no difference among different subgroups. Conclusion: The current analysis suggest that Ino therapy may overcome the impact of Ph-like phenotype in pts with ALL. Confirmation of these findings in a larger cohort and in frontline ALL patients is needed. Disclosures Jabbour: Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding. Sasaki:Pfizer: Consultancy; Otsuka: Honoraria. Jain:Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ravandi:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Consultancy, Research Funding; Macrogenix: Consultancy, Research Funding; Menarini Ricerche: Research Funding; Selvita: Research Funding; Cyclacel LTD: Research Funding. Short:AstraZeneca: Consultancy; Takeda Oncology: Consultancy, Research Funding; Amgen: Honoraria. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Konopleva:Cellectis: Research Funding; Agios: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Ascentage: Research Funding; Eli Lilly: Research Funding; Calithera: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Kisoji: Consultancy, Honoraria; Ablynx: Research Funding; Genentech: Honoraria, Research Funding; Amgen: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Astra Zeneca: Research Funding. Mullighan:Illumina: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: sponsored travel; Pfizer: Honoraria, Other: speaker, sponsored travel, Research Funding; AbbVie: Research Funding; Loxo Oncology: Research Funding; Amgen: Honoraria, Other: speaker, sponsored travel. Kantarjian:Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria, Research Funding; Ariad: Research Funding; Novartis: Research Funding; Amgen: Honoraria, Research Funding; Immunogen: Research Funding; AbbVie: Honoraria, Research Funding; Astex: Research Funding; BMS: Research Funding; Cyclacel: Research Funding; Daiichi-Sankyo: Research Funding; Pfizer: Honoraria, Research Funding; Jazz Pharma: Research Funding; Takeda: Honoraria.

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BCR-ABL1 gene rearrangement as a subclonal change in ETV6-RUNX1–positive B-cell acute lymphoblastic leukemia

Blood Advances ◽

10.1182/bloodadvances.2016000463 ◽

2016 ◽

Vol 1 (2) ◽

pp. 132-138 ◽

Cited By ~ 2

Author(s):

Karen A. Dun ◽

Rob Vanhaeften ◽

Tracey J. Batt ◽

Louise A. Riley ◽

Giuseppe Diano ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Tyrosine Kinase ◽

B Cell ◽

Tyrosine Kinase Inhibitors ◽

Gene Rearrangement ◽

Kinase Inhibitors ◽

Lymphoblastic Leukemia ◽

Rare Occurrence ◽

Key Points ◽

Cell Acute Lymphoblastic Leukemia

Key Points BCR-ABL1 rearrangement as a subclonal change in ETV6-RUNX1–positive B-ALL is a rare occurrence not previously reported. The prognosis of this rare subclonal change has not been determined, yet inclusion of tyrosine kinase inhibitors in treatment is ubiquitous.

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Phase II Study of Blinatumomab and Concurrent Oral Tyrosine Kinase Inhibitor Therapy As Consolidation and Maintenance Therapy for Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Following Chemotherapy-Sparing Induction

Blood ◽

10.1182/blood-2020-137016 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 45-45

Author(s):

Mark B. Geyer ◽

Amber C. King ◽

Justin C. O'Brien ◽

Jae H. Park

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Tyrosine Kinase ◽

Phase Ii ◽

Research Funding ◽

Kinase Inhibitors ◽

Phase Ii Study ◽

Lymphoblastic Leukemia ◽

Philadelphia Chromosome ◽

Multi Agent ◽

Philadelphia Chromosome Positive

Background: Combining oral ABL-targeted tyrosine kinase inhibitors (TKIs) with (w/) multi-agent chemotherapy has improved the long-term disease-free survival of adults w/ Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). However, Ph+ ALL occurs more commonly in older adults, and toxicities of multi-agent chemotherapy, including sequelae of prolonged myelosuppression, are amplified in this population. Others have previously reported rates of morphologic complete response (mCR) approaching 100% among adults w/ Ph+ ALL treated w/ corticosteroids (CS) and dasatinib (DAS) alone as induction therapy, but w/ low rates of minimal residual disease (MRD) negativity by flow cytometry (FACS) and BCR-ABL1 PCR (complete molecular response, CMR) and high rates of relapse in the absence of further consolidation. The bispecific T-cell engager blinatumomab (BLIN) has considerable efficacy in clearing MRD in patients (pts) w/ Ph- B-cell ALL. We have previously reported our institutional experience combining ABL TKIs w/ BLIN in pts w/ Ph+ ALL and MRD, including encouraging safety data and high rates of MRD eradication (King/Geyer et al., Leuk Res, 2019). The ongoing D-ALBA study (GIMEMA LAL2116) is also investigating BLIN + DAS consolidation following 12 weeks of induction (prednisone + DAS followed by DAS), w/out protocol-specified maintenance, and has demonstrated preliminary evidence of efficacy (Chiaretti et al., ASH Meeting, 2019). As such, we designed a phase II study of BLIN as part of a chemotherapy sparing strategy in pts w/ Ph+ ALL (BLISSPHALL), introducing BLIN as early as 6 weeks into treatment for pts in morphologic CR, w/ aim of enhancing early MRD negativity and suppressing resistant clones early in disease course. Study design and methods: Our institution is leading a phase II trial of TKI + BLIN consolidation and maintenance in adults w/ newly-diagnosed Ph+ ALL, w/ potential multicenter expansion (NCT04329325). Pts are eligible if they are ≥18 years-old w/ Ph+ ALL confirmed by cytogenetic or molecular studies, ECOG performance status 0-2, w/out prior therapy for ALL beyond CS, hydroxyurea, or intrathecal chemotherapy, w/out known active extramedullary disease and/or CNS-3 disease, and w/ appropriate organ function. See Figure 1: pts will receive a CS pre-phase (days [d] -6 - 0) followed by modified GIMEMA LAL1205 induction (dexamethasone [DEX] 10 mg/m2 [max 24 mg/d], d1-24, tapered off d25-32) + DAS 140 mg/d (dose adjustments or TKI change permitted per protocol) w/ intrathecal methotrexate (IT MTX) d22, 43 and bone marrow (BM) assessments including FACS and BCR-ABL1 PCR. Pts in mCR on d43 (or optional reassessment ≤ 3 weeks later) will be eligible to proceed to consolidation w/ 3 cycles (C) BLIN 28 mcg/d IVCI, d1-28, concurrent w/ TKI, w/ 14d off BLIN between cycles and BM MRD assessment/IT MTX after each cycle. C1 BLIN + TKI is required to begin inpatient x72 hours. TKI is given continuously including between BLIN cycles. Pts in CMR after consolidation may proceed to maintenance (C4-7 BLIN + TKI, 28d off between cycles). Pts may come off study to proceed to hematopoietic cell transplant (HCT) at any point, though it is recommended such pts receive ≥2C of BLIN + TKI. The primary objective is to determine the proportion of evaluable pts achieving CMR by the end of consolidation (≤ 3C BLIN + TKI). Secondary objectives include safety/toxicity of BLIN + DAS, duration of CMR, incidence of relapse, event-free/overall survival. Exploratory objectives include safety/toxicity of non-DAS TKIs + BLIN, defining patterns/mechanisms of resistance to BLIN+TKI (including ABL kinase mutations), and outcomes among pts not undergoing HCT. The trial utilizes a Simon's minimax two-stage design; 20% CMR rate is considered not promising, a 50% CMR rate is considered promising, and probabilities of type I/II error are set at 0.10/0.10. If ≥ 3 of the first 10 pts achieve CMR we will continue enrollment to max 17 pts. If ≥ 6 pts achieve CMR, then BLIN + TKI will be considered promising for further investigation. The investigators are hopeful this study will add to the currently limited prospective data supporting TKI + BLIN consolidation/maintenance for pts w/ Ph+ ALL and efforts to develop chemotherapy-sparing and immunotherapeutic strategies for older pts w/ ALL. Disclosures Geyer: Amgen: Research Funding. King:Abbvie: Other: advisory board. Park:Novartis: Consultancy; Genentech/Roche: Research Funding; Intellia: Consultancy; Artiva: Membership on an entity's Board of Directors or advisory committees; Fate Therapeutics: Research Funding; Takeda: Consultancy, Research Funding; Servier: Consultancy, Research Funding; AstraZeneca: Consultancy; Allogene: Consultancy; Incyte: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Juno Therapeutics: Research Funding; GSK: Consultancy; Autolus: Consultancy, Research Funding; Minverva: Consultancy; Amgen: Consultancy, Research Funding. OffLabel Disclosure: Blinatumomab is not approved to be given in combination with ABL tyrosine kinase inhibitors for treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia.

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