Outcomes of Patients with Low Variant Allele Fraction JAK2V617F: A 5-Year Retrospective Analysis

Abstract Introduction: JAK2V617F mutation is one of the major criteria in the diagnosis of myeloproliferative neoplasms (MPN). The disease phenotype and outcomes are dependent on variant allele fraction (VAF) of JAK2V617F. Recently, a new entity termed clonal hematopoiesis of indeterminate potential (CHIP) defines patients with normal cell counts and VAF of at least 2%. Outcomes of patients with <2% VAF are scarce and we aimed to retrospectively study characteristics and outcomes of patients with JAK2V617F VAF < 2% compared to patients with VAF 2-10%. Methods: The study population included all patients in the province of British Columbia with JAK2V617F testing performed during 2010-2015. We compared the patient characteristics, disease phenotypes, overall survival (OS), thrombosis-free survival (TFS) and cumulative incidence of thrombotic events between patients with VAF <2% and 2-10%. Parallel real-time quantitative polymerase chain reaction (RQ-PCR) for wild type JAK2 and JAK2V617F was used as detection method. MPN diagnoses were based on the treating physicians' assessment. Results: We identified 216 patients with JAK2V617F VAF < 10%. Twenty-seven patients were excluded due to missing follow-up data. A total of 189 patients were included for final analysis (89 patients with VAF <2% and 100 patients with VAF 2-10%). Patient characteristics, diagnoses and outcomes are shown in the Table. Patients with JAK2V617F >2% have significantly higher rate of splenomegaly, higher platelet counts and higher MPN diagnoses. Ten patients (10.0%) with VAF 2-10% had no hematologic diagnoses, consistent with CHIP, while 24 patients (27.0%) with VAF <2% had no hematologic diagnoses. There were no differences in all outcomes measured including thrombotic complications, progression to hematologic or solid cancers and death. The median follow-up time for the whole cohort was 5.2 years with interquartile range (IQR) 3.5-6.6 years. The 5-year OS were 81.0% for VAF < 2% and 81.7% for VAF 2-10%, log-rank P = 0.922. TFS at 5 years were 71.2% and 69.5%, respectively (P = 0.982). The 5-year cumulative incidences of thrombotic complications (considering death as a competing event) were 8.8% and 11.3%, respectively (Pepe-Mori P = 0.574). Further analysis by clinical diagnoses classified patients into polycythemia vera (PV) 40 (21.2%), essential thrombocythemia (ET) 99 (52.3%), primary myelofibrosis or MPN, NOS (PMF/MPN) 16 (8.5%) and clonal hematopoiesis of indeterminate potential (CHIP) or no hematologic diagnosis 34 (18.0%). Patients with PMF/MPN were significantly older than patients with other diagnoses (median age PV 64.2, ET 64.3, PMF/MPN 80.7 and CHIP 54.1 years, P=0.019). The 5-year OS were: PV 91.4%, ET 90.0%, PMF/MPN 31.3% and CHIP/no hematologic diagnoses 58.7%, P<0.001. TFS at 5 years were 83.1%, 74.7%, 25.0%and 57.4%, respectively, P<0.001. Conclusion: Patients with JAK2V617F VAF < 2% have less splenomegaly and are less likely to have a diagnosis of MPN compared to patients with VAF 2-10%. However, the incidence of thrombotic events was similar between patients with VAF < 2% and 2-10%. In the combined VAF < 10% cohort, PMF/MPN patients were older and had the worst survival outcomes. The mortality in this PMF/MPN group was mostly unrelated to MPN diagnoses. Interestingly, patients with CHIP/no hematologic diagnoses in this study have the next worse OS and TFS. This could be explained by selection bias for performing JAK2 testing in acute or chronically ill patients with reactive changes in the peripheral blood. Table. Table. Disclosures Foltz: Gilead: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Promedior: Research Funding; Incyte: Research Funding.

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Serial Monitoring of Circulating Tumor DNA by Next-Generation Gene Sequencing as a Biomarker of Response and Survival in Patients With Advanced NSCLC Receiving Pembrolizumab-Based Therapy

JCO Precision Oncology ◽

10.1200/po.20.00321 ◽

2021 ◽

pp. 510-524

Author(s):

Jeffrey C. Thompson ◽

Erica L. Carpenter ◽

Benjamin A. Silva ◽

Jamie Rosenstein ◽

Austin L. Chien ◽

...

Keyword(s):

Overall Survival ◽

Progression Free Survival ◽

Circulating Tumor Dna ◽

Variant Allele ◽

Molecular Response ◽

Next Generation ◽

Free Survival ◽

Variant Allele Fraction ◽

Tumor Dna ◽

Allele Fraction

PURPOSE Although the majority of patients with metastatic non–small-cell lung cancer (mNSCLC) lacking a detectable targetable mutation will receive pembrolizumab-based therapy in the frontline setting, predicting which patients will experience a durable clinical benefit (DCB) remains challenging. MATERIALS AND METHODS Patients with mNSCLC receiving pembrolizumab monotherapy or in combination with chemotherapy underwent a 74-gene next-generation sequencing panel on blood samples obtained at baseline and at 9 weeks. The change in circulating tumor DNA levels on-therapy (molecular response) was quantified using a ratio calculation with response defined by a > 50% decrease in mean variant allele fraction. Patient response was assessed using RECIST 1.1; DCB was defined as complete or partial response or stable disease that lasted > 6 months. Progression-free survival and overall survival were recorded. RESULTS Among 67 patients, 51 (76.1%) had > 1 variant detected at a variant allele fraction > 0.3% and thus were eligible for calculation of molecular response from paired baseline and 9-week samples. Molecular response values were significantly lower in patients with an objective radiologic response (log mean 1.25% v 27.7%, P < .001). Patients achieving a DCB had significantly lower molecular response values compared to patients with no durable benefit (log mean 3.5% v 49.4%, P < .001). Molecular responders had significantly longer progression-free survival (hazard ratio, 0.25; 95% CI, 0.13 to 0.50) and overall survival (hazard ratio, 0.27; 95% CI, 0.12 to 0.64) compared with molecular nonresponders. CONCLUSION Molecular response assessment using circulating tumor DNA may serve as a noninvasive, on-therapy predictor of response to pembrolizumab-based therapy in addition to standard of care imaging in mNSCLC. This strategy requires validation in independent prospective studies.

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No Differences in Outcomes Between JAK2 V617F–Positive Patients with Variant Allele Fraction < 2% Versus 2-10%: A 6-Year Province-wide Retrospective Analysis

Clinical Lymphoma Myeloma & Leukemia ◽

10.1016/j.clml.2020.04.010 ◽

2020 ◽

Vol 20 (9) ◽

pp. e569-e578

Author(s):

Wasithep Limvorapitak ◽

Jeremy Parker ◽

Curtis Hughesman ◽

Kelly McNeil ◽

Lynda Foltz ◽

...

Keyword(s):

Retrospective Analysis ◽

Jak2 V617f ◽

Variant Allele ◽

Variant Allele Fraction ◽

Allele Fraction

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Early Disease Relapse after Tyrosine Kinase Inhibitor Treatment Discontinuation in CML Is Related Both to Low Number and Impaired Function of NK-Cells

Blood ◽

10.1182/blood.v124.21.812.812 ◽

2014 ◽

Vol 124 (21) ◽

pp. 812-812 ◽

Cited By ~ 7

Author(s):

Mette Matilda Ilander ◽

Ulla Olsson-Strömberg ◽

Hanna Lähteenmäki ◽

Kasanen Tiina ◽

Perttu Koskenvesa ◽

...

Keyword(s):

T Cells ◽

Nk Cells ◽

Research Funding ◽

Nk Cell ◽

Treatment Discontinuation ◽

Disease Relapse ◽

Cell Counts ◽

Tnf Α ◽

Ifn Γ

Abstract Background: Recent reports suggest that approximately 40% of CML patients who have achieved sustained complete molecular remission are able to stop TKI treatment without disease relapse. However, there are no predictive markers for successful therapy discontinuation. Therefore, we set up an immunological sub-study in the ongoing pan-European EURO-SKI stopping study. Our aim was to identify predictive biomarkers for relapse/non-relapse and to understand more on the mechanisms of immune surveillance in CML. Methods: The EURO-SKI study started in 2012, and patients included were at least three years on TKI and at least one year in MR4 or deeper before the study entry. Basic lymphocyte immunophenotyping (the number of NK-, T- and B-cells) was performed at the time of therapy discontinuation and 1, 6, and 12 months after the TKI stop and in case of relapse (defined as loss of MMR, BCR-ABL1>0.1% IS). In addition, from a proportion of patients more detailed immunophenotypic and functional analyses (cytotoxicity of NK-cells and secretion of Th1 type of cytokines IFN-γ/TNF-α) were done at the same times. Results: Thus far 119 Nordic patients (imatinib n=105, dasatinib n=12, nilotinib n=2) who have discontinued TKI treatment within the EURO-SKI study have been included in the lymphocyte subclass analysis (results are presented from patients who have reached 6 months follow-up). Immunophenotyping analysis demonstrates that imatinib treated patients who were able to maintain remission for 6 months (n=36) had increased NK-cell counts (0.26 vs. 0.15x109cells/L, p=0.01, NK-cell proportion 18.9% vs. 11%, p=0.005) at the time of drug discontinuation compared to patients who relapsed early (before 5 months n=22). Furthermore, the phenotype of NK-cells was more cytotoxic (more CD57+ and CD16+cells and less CD62L+cells), and also their IFN-γ/TNF-α secretion was enhanced (19.2% vs. 13%, p=0.02). Surprisingly, patients who relapsed more slowly (after 5 months, n=16) had similar baseline NK-cell counts (0.37x109cells/L), NK-cell proportion (21.2%), and phenotype and function as patients, who were able to stay in remission. No differences in the NK-cell counts were observed between patients who had detectable or undetectable BCR-ABL1 transcripts at the baseline (0.22 x109cells/L vs. 0.31 x109cells/L, p=0.61). Interestingly, NK-cell count was higher in patients with low Sokal risk score than in patients with intermediate risk (0.33 x109cells/L vs. 0.20 x109cells/L, p=0.04). Furthermore, there was a trend that male patients had a higher proportion of NK-cells than females (21.6% vs. 15.7%, p=0.06). Pretreatment with IFN-α or the duration of imatinib treatment did not have an effect on NK-cell count or proportion. In comparison to the imatinib group, dasatinib treated patients had higher NK-cell counts at the baseline (median 0.52x109cells/L vs. 0.26x109cells/L, p=0.02), and also the proportion of CD27 (median 50% vs. 16%, p=0.01) and CD57 expressing (median 79% vs. 74%, p=0.05) NK-cells was higher. The follow-up time of dasatinib treated patients is not yet long enough to correlate the NK-cell counts with the success of the treatment discontinuation. The absolute number of T-cells or their function did not differ significantly between relapsing and non-relapsing patients at the time of treatment discontinuation. However, both CD4+ and CD8+ T-cells tended to be more mature in patients who stayed in remission compared to patients who relapsed early (CD4+CD57+CD62L- median 5.7% vs. 2.4%, p=0.06, CD8+CD62L+CD45RA+ 13% vs. 26.7%, p=0.05). The analysis of follow-up samples showed that in patients who stayed in remission the Th1 type cytokine (IFN-γ/TNF-α) secretion of CD8+T-cells increased at 6 months compared to baseline (23.6 vs. 18.5%, p=0.07). Same phenomenon was observed in the late relapsing group at relapse compared to baseline (37.9 vs. 13.5%, p=0.03). No similar increase was observed in the early relapsing group. Conclusions: Low NK-cell numbers and poor cytokine secretion may predict early disease relapse after TKI discontinuation. However, patients who relapse later have high numbers of normally functioning NK-cells. Further research (detailed phenotypic analysis of NK- and T-cells including activating and inhibitory receptors and immune checkpoint molecules) and correlation of biomarker data with clinical parameters are ongoing to understand the ultimate determining factors of relapse. Disclosures Själander: Novartis: Honoraria. Hjorth-Hansen:Novartis: Honoraria; Bristol-myers Squibb: Honoraria; Ariad: Honoraria; Pfizer: Honoraria. Porkka:BMS: Honoraria; BMS: Research Funding; Novartis: Honoraria; Novartis: Research Funding; Pfizer: Research Funding. Mustjoki:Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

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Ibrutinib Maintenance (I-M) Following Frontline Intensive Induction in Mantle Cell Lymphoma (MCL): Interim Safety, Response and Sequential MRD Evaluation

Blood ◽

10.1182/blood-2019-126920 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3990-3990 ◽

Cited By ~ 1

Author(s):

Reem Karmali ◽

Jeremy S. Abramson ◽

Deborah M. Stephens ◽

Jeffrey A. Barnes ◽

Jason Kaplan ◽

...

Keyword(s):

Atrial Fibrillation ◽

Research Funding ◽

Residual Disease ◽

Uterine Cancer ◽

Advisory Board ◽

Dynamic Changes ◽

Time Points ◽

Cell Counts ◽

Dose Reductions

Background: MCL carries a poor overall prognosis despite high response rates to induction chemotherapy. Maintenance strategies have impacted survival in MCL but optimal strategies have yet to be defined. Despite profound activity of ibrutinib, a selective BTK inhibitor, in relapsed/refractory MCL, ibrutinib maintenance (I-M) following induction for treatment-naive MCL has not been explored. We report preliminary results of a multicenter phase II trial assessing efficacy and safety of I-M for MCL after frontline induction. Methods: Patients (pts) with MCL with complete or partial response (CR/PR) to frontline chemo-immunotherapy +/- autologous stem cell transplantation (autoSCT) received I-M 560 mg daily for up to 4 years. The primary objective was 3 year PFS rate with I-M. Secondary objectives were PR to CR conversions, median OS after 4 years and toxicity. Measurable residual disease (MRD) assessments using an NGS-MRD Assay (detection resolution of < 1 cell per million; Adaptive Biotechnologies) on peripheral blood and/or PBMCs were planned at 4 time points: prior to I-M initiation and at 1, 6 and 18-24 mo(s) after initiation of I-M. Results: Accrual is complete (n=36). Median age was 60 (range 46-90), 28 pts (78%) were males, 28 (78%) had advanced stage and 9 (25%) had extranodal disease. 18 (50%), 7 (19%) and 11 (31%) had low vs intermediate vs high risk MIPI respectively. For induction, 17 (47%) received bendamustine-rituximab (BR), 18 (50%) a cytarabine-based regimen, and 1 (3%) R-CHOP. 18 (50%) had autoSCT in CR1 prior to enrollment. 33 (92%) and 3 (8%) had CR and PR with induction respectively with 1 PR to CR conversion on I-M. Median follow-up from initiation of induction therapy was 33 mos. With a median follow-up of 24.5 mos from initiation of I-M, 1 pt had disease progression (PD) and 2 others died, 1 from hepatic cholangiocarcinoma 2 years after I-M discontinuation for toxicity (atrial fibrillation) and 1 from unknown cause. 20/36 (56%) pts remain on I-M (median 24 cycles, range 1-52). Sixteen pts discontinued ibrutinib, including 3 for completion of 4 years of I-M. Of the remaining 13 who discontinued, TRAEs accounted for 10 (77%) and the other 3 were for uterine cancer (n=1), PD (n=1), and death of unknown cause (n=1) (Table 1). Atrial fibrillation/atrial flutter accounted for 50% (n=5) of TRAEs that led to I-M discontinuation. 9 (25%) pts required permanent dose reductions for TRAEs with neutropenia (n=3), myalgias (n=2), and fatigue (n=2) being the most common. Collectively, TRAEs led to dose reductions/ interruptions/ discontinuations in 25 (69%) pts. At time of data cut-off, (July 2019), using a trackable dominant clone identified from tissue at diagnosis, MRD was assessed in 12 patients at varying time points (Figure 1). In these 12 pts, 6 were induced with BR, 5 with a cytarabine-based regimen, and 1 with R-CHOP and 5 were consolidated with autoSCT prior to enrollment. Prior to I-M initiation, 9 pts were MRD (-) and 3 had indeterminate MRD status. Indeterminate results corresponded with total cell counts below the level of detection and quantification with our assay. Those with indeterminate MRD status were confirmed to be MRD (-) with subsequent evaluation after 1 month of I-M. 3 of 12 (25%) pts became MRD (+) on I-M. The first reverted back to MRD (-) status and remains MRD (-) with clinical CR on > 3 years of I-M. The second pt was treated with hyperCVAD with PR prior to I-M. This patient required several dose interruptions for neutropenia just prior to MRD detection with clinical PD leading to discontinuation of therapy after 9 months of I-M. The third pt was treated with R-CHOP + autoSCT with PR prior to I-M and maintains a PR despite MRD conversion on > 2 years of I-M. Further analysis of dynamic changes in dominant and non-dominant clones associated with I-M is ongoing. Conclusions: I-M is feasible in MCL pts who respond to frontline chemo-immunotherapy +/- autoSCT with manageable toxicities consistent with the known safety profile of ibrutinib. Guidelines to discontinue I-M for atrial fibrillation were strictly upheld in this protocol though not typical of current practice. NGS can be used to assess MRD with induction and maintenance therapy and demonstrates that most pts are MRD negative after intensive induction. Longer follow-up, evaluation of dynamic changes in MRD, and PFS and OS data are needed to assess clinical relevance of I-M and importance of MRD status, and may support larger, controlled studies. Disclosures Karmali: Gilead/Kite; Juno/Celgene: Consultancy, Speakers Bureau; Takeda, BMS: Other: Research Funding to Institution; Astrazeneca: Speakers Bureau. Abramson:AbbVie Inc, Amgen Inc, Bayer HealthCare Pharmaceuticals, Celgene Corporation, EMD Serono Inc, Genentech, Gilead Sciences Inc, Janssen Biotech Inc, Juno Therapeutics, a Celgene Company, Karyopharm Therapeutics, Kite Pharma Inc, Merck, Novartis, Seattle Gen: Consultancy. Stephens:Karyopharm: Research Funding; Gilead: Research Funding; Acerta: Research Funding. Winter:Merck: Consultancy, Research Funding. Ma:Genentech: Consultancy; Gilead: Research Funding; Astra Zeneca: Consultancy, Research Funding, Speakers Bureau; Acerta: Research Funding; Abbvie: Research Funding; Incyte: Research Funding; Janssen: Consultancy, Speakers Bureau; Kite: Consultancy; Juno: Research Funding; Xeme: Research Funding; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Beigene: Research Funding; Bioverativ: Consultancy; Novartis: Research Funding. Petrich:Abbvie: Employment, Equity Ownership. Kuhr:Adaptive Biotechnologies: Employment, Other: shareholder. Gordon:Zylem LLC: Other: co-founder; research in nanoparticles in cancer; Bayer: Other: Advisory Board; Juno/Celgene: Other: Advisory Board, Research Funding; Gilead: Other: Advisory Board. Pro:Takeda: Consultancy, Honoraria, Other: Travel Expenses; Celgene: Consultancy, Honoraria; Kyowa Hakka Kirin: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Other: Travel Expenses, Research Funding. OffLabel Disclosure: We will discuss results of our trial looking at ibrutinib maintenance in frontline MCL

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Clinical Characteristics and Outcomes of Newly Diagnosed Patients with Adult T-Cell Acute Lymphoblastic Leukemia (T-ALL) and T-Lymphoblastic Lymphoma (T-LL) with Hypercvad Based Regimens

Blood ◽

10.1182/blood.v128.22.2779.2779 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2779-2779

Author(s):

Preetesh Jain ◽

Hagop M. Kantarjian ◽

Farhad Ravandi ◽

Rashmi Kanagal-Shamanna ◽

Joseph D Khoury ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Research Funding ◽

Chromosomal Abnormalities ◽

Lymphoblastic Leukemia ◽

Patient Characteristics ◽

Lymphoblastic Lymphoma ◽

Survival Outcomes ◽

Not Otherwise Specified ◽

T Lymphoblastic Lymphoma

Abstract Introduction: T-cell ALL and T-LL are considered as different spectra of the same neoplastic clone. In various clinical trials of adult ALL, patients with T-ALL and T-LL were combined when analyzing treatment responses and survival outcomes. We have previously reported the results with HCVAD-based regimens in patients with adult ALL. In this study we addressed whether the initial presentation, treatment response, and survival outcomes of adults with T-LL and T-ALL differed when patients were uniformly treated with frontline HCVAD-based regimens at a single institution. Methods: One hundred and fifty previously untreated patients with T-LL (n=54) and T-ALL (n=96) who were treated with HCVAD-based regimens (1992-2016) were included in this analysis. Patient charts were reviewed for initial characteristics, treatment responses including minimal residual disease (MRD) status and survival outcomes; event free (EFS) and overall survival (OS) were analysed. Results: Among 150 patients with previously untreated adult T-ALL/LL, we identified 54 patients (36%) with T-LL and 96 (64 %) with T-ALL. Among patients with available immunophenotype data (n=104), early T precursor (ETP) phenotype was significantly more frequent among patients with T-ALL compared to patients with T-LL (44% vs 19%; p=0.006). The proportion of early, cortical and mature immunophenotype were 2% vs 6%, 31% vs 49% and 16% vs 12% in T-ALL versus T-LL, respectively. The clinical characteristics, response to therapy and outcomes of patients in T-LL versus T-ALL were compared (Table 1 and Figure-1). Patients with T-ALL were slightly older at presentation (median age 37 years [18-67] versus 31 years [17-78]; p=0.07). Patients with T-ALL had significantly higher white blood cell counts, peripheral blood blasts %, bone marrow blasts %, and serum LDH as compared to patients with T-LL. Distribution of chromosomal aberrations was significantly different among the two groups: Diploid karyotype was more commonly encountered in patients with T-LL while patients with T-ALL had more hyperdiploidy and hypodiploidy. Among patients evaluable for response, complete remission (CR) rates were 85% and 95% (p=0.002) in T-LL and T-ALL, respectively. Overall the median follow up times were 72 months (range, 5-243) and 61 months (range, 1-267). Thirty nine (72%) patients with T-LL and 43 (45%) with T-ALL were alive at the time of last follow-up. Patients with T-LL had better outcomes than patients with T-ALL. The 3-year EFS and OS rates were 78% and 74% in patients with T-LLand 53% (p=0.005) and 50% (p=0.001) in patients with T-ALL (Figure 1). Conclusions: In summary, adult patients with T-LL have better outcomes than patient with T-ALL after treatment with HCVAD-based regimens. Additional studies to characterize the genomic profile in tumoral tissues, as well as the pattern of relapses in patients with adult T-LL and T-ALL are ongoing. Table 1 Summary of patient characteristics according to initial diagnosis - T-lymphoblastic lymphoma (T-LL) vs. T-acute lymphoblastic leukemia (T-ALL) *104 patients had full immunophenotype for classification, nos - not otherwise specified, **On available cytogenetic data (47 in T-LL and 82 in T-ALL), of note 3 patients in T-LL and 22 in T-ALL have miscellaneous chromosomal abnormalities Table 1. Summary of patient characteristics according to initial diagnosis - T-lymphoblastic lymphoma (T-LL) vs. T-acute lymphoblastic leukemia (T-ALL). / *104 patients had full immunophenotype for classification, nos - not otherwise specified, **On available cytogenetic data (47 in T-LL and 82 in T-ALL), of note 3 patients in T-LL and 22 in T-ALL have miscellaneous chromosomal abnormalities Disclosures Konopleva: Calithera: Research Funding; Cellectis: Research Funding. Jain:Incyte: Research Funding; Servier: Consultancy, Honoraria; Seattle Genetics: Research Funding; Infinity: Research Funding; Novimmune: Consultancy, Honoraria; Abbvie: Research Funding; Celgene: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Genentech: Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; BMS: Research Funding. Wierda:Acerta: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Gilead: Research Funding; Genentech: Research Funding. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. O'Brien:Janssen: Consultancy, Honoraria; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy.

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Salvage Chemotherapy with Inotuzumab Ozogamicin (INO) Combined with Mini-Hyper-CVD for Adult Patients with Relapsed/Refractory (R/R) Acute Lymphoblastic Leukemia (ALL)

Blood ◽

10.1182/blood.v126.23.3721.3721 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3721-3721 ◽

Cited By ~ 11

Author(s):

Koji Sasaki ◽

Hagop M. Kantarjian ◽

Susan O'Brien ◽

Deborah A Thomas ◽

Farhad Ravandi ◽

...

Keyword(s):

Median Survival ◽

Research Funding ◽

Response Rate ◽

Performance Status ◽

Early Death ◽

Patient Characteristics ◽

Refractory Disease ◽

Post Transplantation ◽

Low Intensity

Abstract Background: Outcome of patients with R/R ALL is very poor. INO is a CD22 monoclonal antibody bound to a toxin, calecheamicin, and has shown single-agent activity in R/R ALL with a response rate of 58% and median survival of 6.3 months. The addition of non-myelosuppressive therapy to effective low-intensity chemotherapy might further improve clinical outcome. Methods: Patients ≥18 years with R/R ALL were eligible. The chemotherapy was lower intensity than conventional hyper-CVAD and referred to as mini-hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 0.5 g/m2 x 4 doses). Rituximab and intrathecal chemotherapy were given for first 4 courses. IO was given on Day 3 of each of the first 4 courses. Patients received INO at 1.8 mg/m2 for cycle 1 followed by 1.3 mg/m2 for subsequent cycles. Results: Forty-eight patients (23 men, 25 women) have been enrolled so far. Patient characteristics and outcome are summarized in Table 1. Median age is 35 years (range 9-87). Median follow-up is 9.4 months (range, 1-27), and patients received a median of 2 cycles (1-8). Of 46 evaluable patients (2 patients, too early to assess response), 5 patients (11%) were refractory to mini-hyper-CVD + INO and died of progressive disease. Early death was encountered in 7 (15%) patients. The overall response rate was 74%: 24 (52%) CR, 8 (17%) CRp, and 2 (4%) marrow CR. Grade 3-4 non-hematological toxicities included infections, mucositis, increased LFTs, and VOD (n=6; 1 in a patient who had prior allo-SCT; 1 at D35 of CAR T-cell; and 3 post allo-SCT following INO therapy). Four (9%) patients were switched early to maintenance therapy due to poor performance status (n=1), infectious complications (n=2), and prolonged myelosuppression (n=1). Nineteen (41%) patients proceeded to receive allo-SCT. At the last follow-up, 20 (43%) patients are alive in response; 2 (4%) too early to assess response; 4 (8%) relapsed post transplantation. 22 (43%) patients died: 7 early death; 5 refractory disease; 5 post relapse after subsequent salvage, 1 post-transplantation VOD, 3 due to post-transplant complications, and 1 in response to IO due to sepsis and multiple organ failure. The 1-year PFS and OS rates were 60% and 46%, respectively. Median survival for patients with CR/CRp/marrow CR was 18 months versus 1 month in patients with refractory disease (p<0.001). Median survival was 17 months in patients with S1, 6 months in patients with S2 and 7 months in patients with S3+ (Figure). Conclusions: The combination of INO with low-intensity mini-hyper-CVD chemotherapy is effective and shows encouraging results in patients with R/R ALL. The risk of VOD should be considered carefully for patients with previous liver damage and transplant candidate. Lower dose schedule of INO are being explored. Table 1. Patient characteristics and outcome Median (range) / No. (%) N=48 Age (yrs) 35 [9-87] Male 23 (48) Performance Status (ECOG) ≥2 7 (15) Salvage Status S1 S1, Primary Ref S1, CRD1<12m S1, CRD1>12m S2 >S3 24 (50) 4 11 9 11 (23) 13 (27) Karyotype Diploid T(4;11) Misc IM/ND 11 (23) 5 (10) 24 (50) 8 (17) CD22, (%) 96 [26-100] CD20 ≥ 20% 10 (21) Response CR 24 (52) CRp 8 (17) CRi 2 (4) ORR 34 (74) No response 5 (11) Early death 7 (15) Too early 2 Figure 1. Survival by salvage number Figure 1. Survival by salvage number Disclosures O'Brien: Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding. Konopleva:Novartis: Research Funding; AbbVie: Research Funding; Stemline: Research Funding; Calithera: Research Funding; Threshold: Research Funding. Cortes:ARIAD Pharmaceuticals Inc.: Consultancy, Research Funding; Teva: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding.

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Single-Tube qPCR Detection and Quantitation of Hotspot Mutations Down to 0.01% Variant Allele Fraction

Analytical Chemistry ◽

10.1021/acs.analchem.1c03716 ◽

2021 ◽

Author(s):

Kerou Zhang ◽

Luis Rodriguez ◽

Lauren Yuxuan Cheng ◽

Michael Wang ◽

David Yu Zhang

Keyword(s):

Variant Allele ◽

Single Tube ◽

Hotspot Mutations ◽

Variant Allele Fraction ◽

Allele Fraction

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Prolonged Lymphocytepenia after Bendamustine with or without Rituximab Treatment in Patients with Relapsed or Refractory Indolent B-Cell and Mantle Cell Lymphoma

Blood ◽

10.1182/blood.v124.21.3066.3066 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3066-3066 ◽

Cited By ~ 3

Author(s):

Hideaki Saito ◽

Dai Maruyama ◽

Akiko Miyagi Maeshima ◽

Shin-ichi Makita ◽

Hideaki Kitahara ◽

...

Keyword(s):

T Cell ◽

B Cell ◽

Research Funding ◽

Marginal Zone ◽

Cell Lymphoma ◽

Median Number ◽

Marginal Zone Lymphoma ◽

Cell Counts ◽

Mantle Cell

Abstract Introduction: Although bendamustine with or without rituximab has demonstrated remarkable efficacy in patients with relapsed or refractory indolent B-cell lymphoma (B-NHL) and mantle cell lymphoma (MCL), previous reports showed that the incidence of lymphocytopenia was higher in patients receiving bendamustine with or without rituximab than in those receiving other conventional cytotoxic chemotherapies such as R-CHOP regimen. However, the length of time until recovery of the decreased lymphocytes and CD4-positive T cells to the baseline upon bendamustine treatment is still unclear. Patients and Methods: We retrospectively analyzed 56 consecutive patients with relapsed or refractory B-NHL and MCL who received bendamustine with or without rituximab at our institution between 2011 and 2014. We analyzed their peripheral blood lymphocytes and CD4-positive T-cell counts at baseline, during, and after bendamustine treatment, the details of infectious events, and their correlations. Results: Thirty-one (55%) patients were male and 25 (45%) female, with a median age of 63 years (range: 36-86). Twenty (35%) patients had follicular lymphoma, 14 (25%) MCL, nine (16%) transformed lymphoma, five (9%) extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue, four (7%) small lymphocytic lymphoma, two (4%) nodal marginal zone lymphoma, and one (2%) each had lymphoplasmacytic lymphoma and low-grade B-NHL, unclassifiable. The median number of prior regimens administered was two (range: 1-9). Twenty-three (41%) of the 56 patients received rituximab in combination with bendamustine. The median number of bendamustine cycles was four (range: 1-6). The median follow-up period was nine months (range: 0-33 months). At baseline, median lymphocyte and CD4-positive T-cell counts were 1,025/µL (range: 270-3,420/µL) and 282/µL (range: 83-645/µL), respectively. After the first cycle, they immediately decreased to 545/µL (range: 60-2,900/µL) and 190/µL (range: 116-635/µL), respectively. The median lymphocyte and CD4-positive T-cell count nadirs during observation were 365/µL (range: 20-1,310/µL) and 93/µL (range: 7-178/µL), respectively. Significantly decreased lymphocyte counts (median: 260 vs. 410/µL) were detected in the patients who received bendamustine with rituximab compared with those who received bendamustine alone (p=0.03). Recovery of lymphocyte and CD4-positive T-cell counts to those at baseline was observed at 7-9 months after the completion of bendamustine with or without rituximab, and median lymphocyte and CD4-positive T-cell counts were 1,045/µL (range: 170-2,580/µL) and 223/µL (range: 47-709/µL), respectively (Figures A, B). The numbers of patients who received prophylaxis against pneumocystis pneumonia (PCP), varicella zoster virus (VZV), and fungal infection were 44 (78%), 37 (66%), and four (7%), respectively, at the physician's discretion. Infectious events were observed in 32 (57%) patients during follow-up. Cytomegalovirus antigenemia was detected in 15 (27%) patients, VZV infection in two (3%), cytomegalovirus colitis in one (2%), and other infectious complications such as sepsis or febrile neutropenia in 20 (35%) patients. Interestingly, all infectious events occurred within nine months after the completion of bendamustine with or without rituximab in patients who received no treatment after bendamustine during follow-up. Conclusion: The results of this analysis revealed that the majority of relapsed or refractory patients with indolent B-NHL and MCL showed prolonged lymphocytopenia and low CD4-positive T-cell counts, for at least 7-9 months, after the completion of bendamustine with or without rituximab. Because lymphocytopenia, especially low CD4-positive T-cell counts, may increase the risk of opportunistic infections, the prophylaxis against PCP and VZV deserves consideration for at least 7-9 months after bendamustine treatment. Further investigations, especially a prospective study, are needed to confirm our results. Figure A: Figure A:. Figure B: Figure B:. Box plots of lymphocyte counts (Figure A) and CD4-positive T-cell counts (Figure B) among patients who were treated with bendamustine with or without rituximab. Disclosures Maruyama: Eisai Co., Ltd: Honoraria. Kobayashi:Boehringer Ingelheim GmbH: Research Funding; ARIAD Pharmaceuticals, Inc.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding. Tobinai:Eisai Co., Ltd.: Research Funding; SymBio Pharmaceuticals Ltd.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding.

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Idarubicin and Cytarabine Combined with Clofarabine or Fludarabine for the Treatment of Newly Diagnosed Acute Myeloid Leukemia: Interim Result of a Phase II Clinical Trial

Blood ◽

10.1182/blood.v126.23.2508.2508 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2508-2508

Author(s):

Paul B. Koller ◽

Koji Sasaki ◽

Farhad Ravandi ◽

Guillermo Garcia-Manero ◽

Susan O'Brien ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Research Funding ◽

Patient Characteristics ◽

Interim Result ◽

Newly Diagnosed ◽

Younger Patients ◽

Award Recipient ◽

Acute Myeloid

Abstract Background: The combination of 7+3 with a purine nucleoside analogue improved overall survival (OS) in patients with acute myeloid leukemia (AML). We randomized patients to receive either clofarabine (CIA) or fludarabine (FIA) combined with idarubicin and cytarabine. Methods: Patients who were diagnosed with non-CBF AML or non-APL AML were eligible and were randomized using a Bayesian design to one of the following two induction chemotherapy regimens: CIA (clofarabine 15 mg/m2 IV daily for 5 days, idarubicin 10 mg/m2 IV daily for 3 days, cytarabine 1,000 mg/m2 IV daily for 5 days) or FIA (fludarabine 30 mg/m2 IV daily for 5 days, idarubicin 10 mg/m2 IV daily for 3 days, cytarabine 1,000 mg/m2 IV daily x 5 days). Patients could proceed to up to 6 cycles of consolidation with the same drugs according to an attenuated schedule. Results: One-hundred-fifty-eight patients (97 patients, CIA; 61 patients, FIA) were treated so far. Patient characteristics and outcome are summarized in Table 1. Median age is 53 years (range, 20-66) in CIA and 49 years (range, 18-66) in FIA. All patients were evaluable for response. Responses are summarized in Table 1. MRD negativity was observed in 43 (74%) patients treated with CIA and in 19 (35%) patients treated with FIA (p=0.049). Median follow up is 21 months and 16 months for patients treated with CIA and FIA, respectively. Treatment was well tolerated with 8-week mortality rates of 1% and 2%, for patients treated with CIA and FIA respectively. The overall median EFS and OS for the whole population were 12 months and 25 months, respectively. Median EFS for patients treated with CIA and FIA was 14 months and 11 months, respectively (p=0.81). No difference in OS between CIA and FIA was observed: the 2-year OS rates were 48% and 53% (p=0.45), respectively. Furthermore, there was no difference in survival whether patients were censored or not at the time of transplantation. Compared to IA regimen in similar patients population, the triplet (FIA and CIA) showed an improvement in 2-year EFS (60% vs 34%; p=0.05) and a trend for better survival (40% vs 32%; p=0.5) in younger patients (40 years and younger). Conclusions: The combination of clofarabine or fludarabine to idarubicin and cytarabine is safe and effective with high CR and negative MRD rates in patients with newly diagnosed AML. Particularly in younger patients, CIA or FIA can lead to a superior outcome compared to 3+7. Table 1. Patient characteristic and outcome CIA N= 97 (61%) FIA N= 61 (39%) P Median age, y 53 [20-66] 49 [18-66] NS PS ≥ 1 79 (81) 48 (79) NS Hemoglobin, g/dL 9.4 [7.3-13.1] 9.2 [7.8-11.4] NS Platelets x 109/L 37 [1-1069] 40 [5-399] NS WBC x 109/L 3.6 [0.6-103.0] 4.1 [0.5-59.4] NS blast (PB) 11 [0-92] 10 [0-94] NS blast (BM) 52 [1-96] 50 [11-96] NS Creatinine, mg/dL 0.79 [0.34-1.35] 0.79 [0.49-1.72] NS LDH, IU/L 819 [325-11952] 684 [231-12042] NS Bilirubin, mg/dL 0.6 [0.2-1.9] 0.5 [0.2-1.5] 0.03 Cytogenetic # evaluable 97 61 NS Diploid 46 (47) 26 (43) -5/-7 or complex 25 (26) 19 (31) Misc 26 (27) 16 (26) FLT3-ITD, # evaluable 94 61 NS Mutated 20 (21) 11 (18) NPM1, # evaluable 90 55 0.05 Mutated 28 (31) 9 (16) Response # evaluable 97 61 0.347 ORR 82 (85) 48 (79) CR 70 (72) 41 (67) CRp 9 (10) 6 (10) PR 1 (1) 1 (2) MRD Negativity 43/58 (74) 19/35 (54) 0.049 Overall MRD Negativity 54/64 (84) 24/37 (65) 0.024 CR/CRp > SCT 33/79 (42) 23/47 (49) 0.435 Death (on study) 2 (2) 1 (2) NS 4-week mortality 0 (0) 1 (2) NS 8-week mortality 1 (1) 1 (2) NS Median F/U (m) 21.3 [0.9-44.7] 16.3 [4.3-42.0] NS Events, # evaluable 97 61 NS Events 51 (53) 31 (51) Primary failure 15 (15) 13 (21) Relapse 26/82 (32) 13/48 (27) Death in CR 6 (9) 4 (7) Disclosures O'Brien: Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding. Cortes:Novartis: Consultancy, Research Funding; BerGenBio AS: Research Funding; Teva: Research Funding; BMS: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy. Pemmaraju:LFB: Consultancy, Honoraria; Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding. Chahoud:American Society of Hematology (ASH): Other: 2015 HONORS Award recipient.

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Re-Mineralization of Large Pelvic Lytic Lesions By CT Imaging in Patients with Multiple Myeloma: The Arkansas Experience

Blood ◽

10.1182/blood.v126.23.4193.4193 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4193-4193

Author(s):

Meera Mohan ◽

Rohan Samant ◽

Larry J Suva ◽

Corey O Montgomery ◽

Daisy V. Alapat ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Bone Destruction ◽

Patient Characteristics ◽

University Of Arkansas ◽

Medical Sciences ◽

Advisory Committees ◽

Osteolytic Lesions ◽

Lytic Lesions

Abstract INTRODUCTION Profound osteolytic lesions are a hallmark of multiple myeloma (MM) bone disease. Bone destruction is associated with severely unbalanced bone remodeling, secondary to the secretion of osteoclast activating factors and significant osteoblast suppression. Lytic lesions of the pelvis are relatively common in MM patients and contribute to increase morbidity due to the high risk of fracture that frequently demands surgical intervention. Since we observed significant improvements in the pelvic CT of patients following total therapy 4 (TT4) we retrospectively analyzed the appearance on pelvic osteolytic lesions by CT during TT4 treatment for myeloma. METHODS The UAMS Myeloma data base was interrogated to identify patients enrolled on the TT4 trial. TT4 is a protocol designed for low risk MM patients as defined by a baseline plasma cell GEP score < than 0.66. The treatment protocol includes two induction chemotherapy cycles followed by tandem autologous bone marrow transplantation, two consolidation cycles and 3 years of maintenance. During treatment, patients were exposed to alkylating agents, IMIDS and proteasome inhibitor agents as well as bisphosphonates. Baseline pelvic osteolytic lesions with > 1 cm in minimal diameter identified by PET/CT or CT of the pelvis were compared to the most recent radiological study available for the same subject. All identified cases were reviewed by radiology faculty to confirm the baseline and follow-up reported findings. Radiological findings were correlated with disease status, molecular subgroup, PET scanning and MRI. RESULTS Sixty-three (63) patients, with a median age of 62 years, were identified for this analysis. Baseline patient characteristics are shown in Table 1. With a median follow up of 41 months, CT studies indicate that 44% (28/63) of patients with large baseline pelvic lytic lesions achieved re-accumulation of radio-dense mineralized tissue at the lytic site. Sixty-eight percent of such patients reached at least VGPR. The average size of the lytic lesions that re-mineralized was 4.0 cm (minimum 1.3 cm - maximum 10 cm). Baseline GEP-defined molecular subgroups and cytogenetic distribution was not different from the entire patient population of TT4. CONCLUSION This study clearly shows that mineral redeposition in large pelvic lytic lesions of MM patients on TT4 is achievable in a significant proportion of individuals. We observed that the amount of re-mineralization was prominent in pelvic lytic lesions with cortical bone destruction. Since flat bones, such as the pelvis, are formed via intramembranous ossification further investigation of the mechanism responsible for this effect is warranted at skeletal sites with different regenerative capacity. These data also suggest that, contrary to much dogma, MM bone lesions can regain matrix mineralization capacity. Table 1. Baseline Patient Characteristics n/N (%) Male 43/63 (69%) IgA Isotype 11/63 (17.5%) IgD Isotype 1/63 (1.6%) IgG Isotype 36/63 (57.1%) Nonsecretory 1/63 (1.6%) Light Chain Isotype 14/63 (22.2%) LDH > = 190 U/L 8/63 (12.7%) Abnormal Cytogenetics 44/63 (69.8%) GEP CD-1 subgroup 4/64 (6.3%) GEP CD-2 subgroup 17/64 (26.6%) GEP HY subgroup 24/64 (37.5%) GEP LB subgroup 8/64 (12.5%) GEP MF subgroup 1/64 (1.6%) GEP MS subgroup 2/64 (3.1%) GEP PR subgroup 5/64 (7.8%) Disclosures Mohan: University of Arkansas for Medical Sciences: Employment. Samant:University of Arkansas for Medical Sciences: Employment. Suva:University of Arkansas for Medical Sciences: Employment. Montgomery:University of Arkansas for Medical Sciences: Employment. Alapat:University of Arkansas for Medical Sciences: Employment. Morello:University of Arkansas for Medical Sciences: Employment. van Rhee:University of Arkansa for Medical Sciences: Employment. Waheed:University of Arkansas for Medical Sciences: Employment. Thanendrarajan:University of Arkansas for Medical Sciences: Employment. Schinke:University of Arkansas for Medical Sciences: Employment. Heuck:Millenium: Other: Advisory Board; Celgene: Consultancy; Foundation Medicine: Honoraria; Janssen: Other: Advisory Board; University of Arkansas for Medical Sciences: Employment. Jethava:University of Arkansas for Medical Sciences: Employment. Johann:University of Arkansas for Medical Sciences: Employment. Barlogie:University of Arkansas for Medical Sciences: Employment. Davies:University of Arkansas for Medical Sciences: Employment; Celgene: Consultancy; Janssen: Consultancy; Millenium: Consultancy; Onyx: Consultancy. Morgan:CancerNet: Honoraria; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; University of Arkansas for Medical Sciences: Employment; MMRF: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Weismann Institute: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Zangari:Novartis: Research Funding; Millennium: Research Funding; Onyx: Research Funding; University of Arkansas for Medical Sciences: Employment.

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