Randomized Phase II Study of Two Schedules of Flavopiridol (Alvocidib, F) Given as Timed Sequential Therapy (TST) Wtih Ara-C and Mitoxantrone (FLAM) for Adults with Newly Diagnosed, Poor-Risk Acute Myelogenous Leukemia (AML)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 186-186 ◽  
Author(s):  
Judith E. Karp ◽  
John M. Pagel ◽  
B. Douglas Smith ◽  
Jacqueline M Greer ◽  
D. Michelle Drye ◽  
...  
Keyword(s):  
Phase Ii ◽  
Kinase Inhibitor ◽  
Conflicts Of Interest ◽  
Disease Free Survival ◽  
Sequential Therapy ◽  
Myelogenous Leukemia ◽  
Newly Diagnosed ◽  
Hematopoietic Stem ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Poor Risk

Abstract Abstract 186 Acute Myeloid Leukemia - Therapy, excluding Transplantation: Pediatric and Adult AML Therapy F is a protein bound, cytotoxic, cyclin dependent kinase inhibitor. A prior Phase II trial of TST with FLAM, with F given by one hour bolus daily × 3 for adults with newly-diagnosed AML with poor-risk features demonstrated that the complete remission (CR) rate was 30/45 (67%) with median overall survival (OS) and disease-free survival (DFS) for CR patients being 12.6 and 13.3 months, respectively. We now compare FLAM using bolus F (50 mg/m2 daily × 3; Arm A) vs. FLAM using F given by pharmacologically-derived “hybrid” schedule (30 mg/m2 bolus over 30 min followed by 40 mg/m2 in a 4 hr infusion daily × 3; Arm B) in 70 newly-diagnosed AML patients (pts) with poor-risk features. Results: Pt demographics are presented below. Age # < 50 Secondary AML Adverse Genetics MDS/MPD t-AML Single Complex Flt3 ARM A (n = 36) 59ü(24–78) 3 19 5 6 13 3 Total 24/36 = 67% Total 22/36 = 61% ARM B (n = 34) 58ü(20–73) 5 16 9 8 10 5 Total 25/34 = 74% Total 23/34 = 68% Grade > 3 tumor lysis occurred in 4/70 (6%) with 1 death (A), 1 transient hemodialysis (A), 1 transient hyperkalemia (B), and 1 discontinuation of therapy (B). Four pts (6%) died from regimen toxicity before day 60 (1 A, 3 B). Median time for ANC >500/uL was Day 33 (range 22–71), and platelets > 50,000/uL Day 30 (21-80) for both arms. CR rate in Arm A is 23/36 (64%) including 16/24 (67%) with prior MDS and 13/19 (68%) with adverse cytogenetics and 3/3 (100%) with FLT3-ITD. CR rate in Arm B is 24/34 (71%) including 16/24 (67%) with prior MDS, 12/18 (67%) with adverse cytogenetics, and 4/5 (80%) with FLT3-ITD. As of 7/1/10, 20/23 Arm A CR pts have received chemotherapy and/or allogeneic hematopoietic stem cell transplantation (HCT) in CR: 15/23 (65%) of these pts remain alive and in continuous CR for up to 14+ months, 2 relapsed 4 months post-HCT, and 2 died (1 FLAM consolidation, 1 HCT). Similarly, 20/24 Arm B CR pts have received chemotherapy and/or HCT in CR: 12/20 (60%) remain alive and in continuous CR for up to 18+ months. Of Arm B pts receiving FLAM consolidation, 1 relapsed at 2 months, 1 died at 8 months of cardiac failure, and 2 died during therapy. Three were unable to receive a second cycle and 1 refused. Overall, 51/70 (73%) of all pts and 40/47 (85%) of CR pts are alive 2+ - 19+ months after FLAM. Conclusions: TST with FLAM induces CR in >60% of newly diagnosed, poor-risk AML pts, including those with prior MDS and adverse genetics. There does not appear to be major difference in toxicity or responses between the two F schedules (bolus vs. “hybrid” bolus-infusion). Thus far, allogeneic HCT has been successfully undertaken in 21/47 (45%) of first CR patients, median age 57 (20-64), with 2 early relapses and 1 death from GVHD. Bolus F may be easier to administer than hybrid F and is therefore recommended for further study in newly diagnosed AML pts. These salutary results of FLAM in poor-risk pts will now be evaluated broadly in adults with AML and compared to traditional cytotoxic chemotherapy induction regimens. Disclosures: No relevant conflicts of interest to declare.

Randomized Phase II Trial of Timed-Sequential Therapy (TST) with Flavopiridol (Alvocidib), Ara-C and Mitoxantrone (FLAM) Versus “7+3” for Adults Ages 70 Years and Under with Newly Diagnosed Acute Myeloid Leukemia (AML)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 47-47 ◽  
Author(s):  
Joshua F. Zeidner ◽  
Jonathan M. Gerber ◽  
Amanda Blackford ◽  
Mark Litzow ◽  
Matthew C. Foster ◽  
...  
Keyword(s):  
Phase Ii ◽  
Residual Disease ◽  
Tumor Lysis Syndrome ◽  
Disease Free Survival ◽  
Adult Patients ◽  
Clinical Relapse ◽  
Newly Diagnosed ◽  
Aldh Activity ◽  
Hematopoietic Stem ◽  
Poor Risk

Abstract Abstract 47 Background In adults with newly diagnosed, poor-risk AML we previously demonstrated that induction therapy with Flavopiridol in combination with Ara-C and Mitoxantrone (FLAM,) in a timed-sequential manner, yields complete remission (CR) rates of 67% and median disease-free survival (DFS) of 13.6 months. These data suggest that FLAM might improve outcomes relative to standard “7+3” in newly diagnosed AML with poor-risk features. Thus, we are conducting a phase II randomized trial comparing the CR rates with FLAM vs. 7+3 induction for all newly diagnosed adult patients with AML with intermediate and poor-risk features. We also previously identified a population of CD34+CD38− cells with intermediate aldehyde dehydrogenase (ALDH) activity that appears to represent a leukemic stem cell (LSC) population. We are examining the effects of FLAM vs. 7+3 in eradicating this LSC population and determining if persistence of LSC's predicts for relapse. Objectives The primary objective is to compare the rate of CR after 1 cycle of FLAM vs. 1 cycle of 7+3. The secondary objectives are to compare toxicities, survival rates, and presence or absence of minimal residual disease (MRD) after both induction regimens. Methods All newly diagnosed adult patients aged 18–70 without favorable risk features were randomized in a 2:1 fashion between FLAM and 7+3 at 90 mg/m2 of Daunorubicin. To achieve balanced randomization, patients were stratified by age, secondary AML and leukocyte count. CD34+ cell subsets were analyzed by flow cytometry for CD38 expression and ALDH activity by Aldefluor. The trial is ongoing. Results To date, 62 patients are evaluable for the primary end point. Demographics and results are depicted in table 1. Patient characteristics were similar in both arms, although there were more patients with poor risk features in the FLAM arm than 7+3. Overall grade > 3 toxicity was similar between both arms. However, there were 3 cases of grade > 3 tumor lysis syndrome (TLS) with FLAM, with 1 death, vs. 0 with 7+3. There were also 3 deaths with FLAM before day 60 vs. 0 with 7+3. CR rate with FLAM was 68% (28/41), with 1 cycle of 7+3 was 48% (10/21) (p = 0.17), and with 2 cycles (7+3 + 5+2) was 52% (11/21). CR rates based on specific risk factors are depicted in table 2. There was a trend toward improved CR rates in patients with adverse genetics with FLAM (p = 0.17). Putative AML LSC's were distinguished from normal hematopoietic stem cells based on ALDH activity. The persistence of putative LSC's in patients after therapy was highly predictive of subsequent clinical relapse. Conclusions Based on the current CR rate of 68%, FLAM holds promise as a therapeutic option for patients with newly diagnosed AML with intermediate and poor risk features. In this preliminary analysis, there is a suggestion that FLAM leads to higher CR rates in patients with adverse genetics than 7+3. Additionally, the detection of MRD consisting of a residual putative LSC population strongly portended subsequent relapse, even in patients without evidence of leukemia. Disclosures: Off Label Use: Flavopiridol (Alvocidib) is an anti-leukemia agent.

Phase II Study of Timed Sequential Therapy (TST) with Topotecan, Cytosine Arabinoside (ARA-C), and Mitoxantrone (TAM) Induction Therapy Followed by Non-Cross-Resistant Consolidation Chemotherapy for Adults with Newly Diagnosed Acute Myelogenous Leukemia (AML).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 876-876
Author(s):  
Ivana Gojo ◽  
Lawrence Morris ◽  
Chuanfa Guo ◽  
Meyer Heyman ◽  
Michael Tidwell ◽  
...  
Keyword(s):  
Median Time ◽  
Induction Therapy ◽  
Topoisomerase I ◽  
Multiorgan Failure ◽  
Significant Risk ◽  
Pulmonary Hemorrhage ◽  
Disease Free Survival ◽  
Myelogenous Leukemia ◽  
Newly Diagnosed ◽  
Poor Risk

Abstract Clinical results in AML continue to need improvement, particularly for age ≥60, prior MDS or secondary AMLs, and AMLs with adverse cytogenetics (CG) where complete remission (CR) rates are <50% and cure rates are <10%. In an attempt to improve these outcomes, we developed a TST regimen of the topoisomerase I inhibitor Topotecan with ara-C and Mitoxantrone (TAM) as induction therapy for adults with newly diagnosed AML: T, 4.5 mg/m2 IV continuous infusion (CI) over 72 hrs days (d) 1-3; A, 2 gm/m2 IV CI over 72 hrs d 3-5; and M, 40 mg/m2 IV d 10. CR patients with poor risk features received consolidation TST with T, 4.5 mg/m2 CI over 72 hrs d 1-3; A, 2 gm/m2 IV CI over 72 hrs d 3-5; and etoposide (E), 300 mg/m2 IV CI over 72 hrs d 10-12 (TAE); CR patients without poor risk features received consolidation TST with A, 2 gm/m2 CI over 72 hrs d 1-3 and 10-12; and idarubicin (I) 12 mg/m2 IV d 1,2,3 (AIA). From 04/02-2/04, 60 newly diagnosed AML patients (median age 49 yrs, 21–79) received TAM induction chemotherapy. Of 60 pts, 47 (78.5%) had at least one poor prognostic feature: age ≥60, 16 (27%); adverse CG, 28 (47%); MDS/AML, 10 (17%); secondary AML, 3 (5%); and/or WBC >25,000/μl, 23 (38.5%). Of the 41 (68.5%) pts who achieved CR, 32 (78%) received consolidation TST (22 TAE; 10 AIA). The remaining 9 pts received alloBMT (2), alternate therapy (5), or no consolidation (2) due to incomplete reversal of organ damage. Furthermore, 8 pts who finished 2 cycles of TST subsequently received alloBMT (3), autoBMT (2) and maintenance Zarnestra (3). Median overall survival (OS) for all pts is 10.1 mos, with 1yr survival 45.7% (95% CI; 32.5%–58.9%). On multivariate analysis, only antecedent MDS was a significant risk factor for poor OS (HR=2.5, 95% CI 1.13–5.65; p=0.02). For patients who achieved CR, median disease free survival (DFS) was 9.9 mos (95% CI; 5.8–18.2) with 1yr DFS 45.9% (95% CI; 29.4%–62.4%). Preceding MDS (p=0.02), adverse CG (p=0.04) and age ≥50 (p=0.06) were associated with low CR. Induction and consolidation mortality were <10%. Median time for ANC >100/μl was 28 days (22–56) and platelets >50,000/μl was 30 days (22–81) following TAM. For consolidation, median time to ANC >100/μl was 27.5 days (19–48) for TAE and 39 days (26–43) for AIA, and plts >50,000/μl 34 days (19–87) for TAE and 54 days (33–79) for AIA. Toxicities during induction and consolidation were generally ≤grade 3 and consisted of infection (bacteremias, pneumonias), oral and/or GI mucositis, transient elevation in liver function tests, reversible renal insufficiency. Pulmonary hemorrhage (1), GI bleed (3), CNS bleed/infarct (2) and decreased ejection fraction (2) occured during induction/consolidation but resolved. Causes of death during induction were sepsis/multiorgan failure (3), progressive fungal pneumonia (1), grade 5 marrow aplasia (1); during consolidation multiorgan failure (1), renal failure/sepsis (1), pulmonary hemorrhage (1). In summary, TAM induction for AML is associated with significant CR rates and acceptable toxicity, but did not appear to overcome the poor DFS and OS in a high-risk group of adults.

Disruption of the Peripheral Lymphoid Niche Contributes to Lymphopenia in CML Patients Undergoing Imatinib Treatments

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5165-5165
Author(s):  
Stephanie Thiant ◽  
Moutuaata M.Moutuou ◽  
Philippe Laflamme ◽  
Radia Sidi Boumedine ◽  
Fanny Larochelle ◽  
...  
Keyword(s):  
Stem Cells ◽  
Imatinib Mesylate ◽  
Median Time ◽  
Kinase Inhibitor ◽  
Conflicts Of Interest ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Hematopoietic Stem ◽  
Gm Csf

Abstract PURPOSE: Chronic myelogenous leukemia (CML) is a disorder affecting early hematopoietic stem cells (HSC) and is characterized by excessive proliferation and accumulation of myeloid progenitors and progeny in the periphery. During the chronic phase of the disease, CML patients are normally at low risk of developing infections but such complications tend to rise during the progression of the disease. Gleevec (imatinib mesylate) is currently administered as first line therapy for patients with Philadelphia chromosome-positive CML. Despite the relative high specificity of tyrosine kinase inhibitor (TKI) treatment towards the BCR-ABL fusion protein, off-target multikinase inhibitory effects occur and can interfere with normal hematopoiesis. This study was conducted to evaluate how myeloid and lymphoid immune homeostasis are affected by Imatinib mesylate. METHODS: Healthy volunteer donors (n=25) and CML patients were recruited during their first visit at our CML clinic. Seven CML patients were treated with Imatinib (400mg). The median time of Gleevec treatment was 2.9 years (range: 0.5-10.9). The median time of remission post TKI was 1.1 years (range: 0.3-3). Phenotypic analysis of dendritic cell (DCs) subsets: plasmacytoid (pDCs) and myeloid type 1, 2 and 3 (mDC1, mDC2, mDC3) were evaluated by flow cytometry. Percentage and absolute numbers of naive and memory CD4+ and CD8+ T cells, NK cells and B cells were also evaluated. DCs were differentiated from purified CD34+ cells culturedwith GM-CSF (800 U/ml) or Flt3-L (50ng/ml), IL-4 (10 U/ml) and TNFa (50 U/ml), in the presence of varying concentrations of Imatinib mesylate (0 to 5µM/mL). TCR and IL-7 signaling were evaluated based on ERK-phosphorylation (-p) and STAT5-p after incubation with 3µM of Imatinib. RESULTS AND CONCLUSION: At diagnosis, several CML patients have a deficit in DCs resulting from a severe skewing affecting BM progenitor cells. After initiating Gleevec therapy, normalization of stem cell progenitors occurs but DC counts remain well below normal levels in all CML patients. We demonstrated a direct and dose dependent interference of Imatinib on GM-CSF and Flt3-L pathways for DC differentiation from CD34+ stem cells. For T lymphocytes, Imatinib interfered with TCR and IL-7 signaling through the inhibition of ERK and STAT5 phosphorylation respectively. The failure to maintain adequate numbers of DCs combined to diminished homeostatic response to cytokines and TCR stimuli explains T cell lymphopenia in these patients. Such immune dysfunction is at least in part responsible for infectious complications that are often increased in patients treated with Imatinib. Disclosures No relevant conflicts of interest to declare.

scholarly journals Identification of novel regulators of hematopoietic stem cell development through refinement of stem cell localization and expression profiling

Blood ◽  
2009 ◽  
Vol 114 (21) ◽  
pp. 4645-4653 ◽  
Author(s):  
Maria I. Mascarenhas ◽  
Aimée Parker ◽  
Elaine Dzierzak ◽  
Katrin Ottersbach
Keyword(s):  
Gene Expression ◽  
Stem Cell ◽  
Expression Profiling ◽  
Gene Expression Analysis ◽  
Kinase Inhibitor ◽  
Cyclin Dependent Kinase ◽  
Hematopoietic Stem ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Cell Localization ◽  
Before And After

Abstract The first adult-repopulating hematopoietic stem cells (HSCs) are detected starting at day 10.5 of gestation in the aorta-gonads-mesonephros (AGM) region of the mouse embryo. Despite the importance of the AGM in initiating HSC production, very little is currently known about the regulators that control HSC emergence in this region. We have therefore further defined the location of HSCs in the AGM and incorporated this information into a spatial and temporal comparative gene expression analysis of the AGM. The comparisons included gene expression profiling (1) in the newly identified HSC-containing region compared with the region devoid of HSCs, (2) before and after HSC emergence in the AGM microenvironment, and (3) on populations enriched for HSCs and their putative precursors. Two genes found to be up-regulated at the time and place where HSCs are first detected, the cyclin-dependent kinase inhibitor p57Kip2/Cdkn1c and the insulin-like growth factor 2, were chosen for further analysis. We demonstrate here that they play a novel role in AGM hematopoiesis. Interestingly, many genes involved in the development of the tissues surrounding the dorsal aorta are also up-regulated during HSC emergence, suggesting that the regulation of HSC generation occurs in coordination with the development of other organs.

Phase II trial of flavopiridol, a cyclin dependent kinase inhibitor, in untreated metastatic malignant melanoma

2004 ◽  
Vol 22 (3) ◽  
pp. 315-322 ◽  
Author(s):  
Susan Burdette-Radoux ◽  
Richard G. Tozer ◽  
Reinhard C. Lohmann ◽  
Ian Quirt ◽  
D. Scott Ernst ◽  
...  
Keyword(s):  
Malignant Melanoma ◽  
Phase Ii ◽  
Kinase Inhibitor ◽  
Phase Ii Trial ◽  
Metastatic Malignant Melanoma ◽  
Cyclin Dependent Kinase ◽  
Cyclin Dependent Kinase Inhibitor

Efficacy of STI571, an Abl tyrosine kinase inhibitor, in conjunction with other antileukemic agents against Bcr-Abl–positive cells

Blood ◽  
2000 ◽  
Vol 96 (9) ◽  
pp. 3195-3199 ◽  
Author(s):  
J. Tyler Thiesing ◽  
Sayuri Ohno-Jones ◽  
Kathryn S. Kolibaba ◽  
Brian J. Druker
Keyword(s):  
Clinical Trials ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Kinase Inhibitor ◽  
Single Agent ◽  
Myelogenous Leukemia ◽  
Hematopoietic Stem ◽  
Abl Tyrosine Kinase ◽  
Abl Tyrosine Kinase Inhibitor

Abstract Chronic myelogenous leukemia (CML), a malignancy of a hematopoietic stem cell, is caused by the Bcr-Abl tyrosine kinase. STI571(formerly CGP 57148B), an Abl tyrosine kinase inhibitor, has specific in vitro antileukemic activity against Bcr-Abl–positive cells and is currently in Phase II clinical trials. As it is likely that resistance to a single agent would be observed, combinations of STI571 with other antileukemic agents have been evaluated for activity against Bcr-Abl–positive cell lines and in colony-forming assays in vitro. The specific antileukemic agents tested included several agents currently used for the treatment of CML: interferon-alpha (IFN), hydroxyurea (HU), daunorubicin (DNR), and cytosine arabinoside (Ara-C). In proliferation assays that use Bcr-Abl–expressing cells lines, the combination of STI571 with IFN, DNR, and Ara-C showed additive or synergistic effects, whereas the combination of STI571 and HU demonstrated antagonistic effects. However, in colony-forming assays that use CML patient samples, all combinations showed increased antiproliferative effects as compared with STI571 alone. These data indicate that combinations of STI571 with IFN, DNR, or Ara-C may be more useful than STI571 alone in the treatment of CML and suggest consideration of clinical trials of these combinations.

scholarly journals The quiescent fraction of chronic myeloid leukemic stem cells depends on BMPR1B, Stat3 and BMP4-niche signals to persist in patients in remission

Haematologica ◽  
2020 ◽  
Vol 106 (1) ◽  
pp. 111-122 ◽  
Author(s):  
Sandrine Jeanpierre ◽  
Kawtar Arizkane ◽  
Supat Thongjuea ◽  
Elodie Grockowiak ◽  
Kevin Geistlich ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Tyrosine Kinase ◽  
Stromal Cells ◽  
Kinase Inhibitor ◽  
Bmp Signaling ◽  
Myelogenous Leukemia ◽  
Leukemic Stem Cells ◽  
Hematopoietic Stem

Chronic myelogenous leukemia arises from the transformation of hematopoietic stem cells by the BCR-ABL oncogene. Though transformed cells are predominantly BCR-ABL-dependent and sensitive to tyrosine kinase inhibitor treatment, some BMPR1B+ leukemic stem cells are treatment-insensitive and rely, among others, on the bone morphogenetic protein (BMP) pathway for their survival via a BMP4 autocrine loop. Here, we further studied the involvement of BMP signaling in favoring residual leukemic stem cell persistence in the bone marrow of patients having achieved remission under treatment. We demonstrate by single-cell RNA-Seq analysis that a sub-fraction of surviving BMPR1B+ leukemic stem cells are co-enriched in BMP signaling, quiescence and stem cell signatures, without modulation of the canonical BMP target genes, but enrichment in actors of the Jak2/Stat3 signaling pathway. Indeed, based on a new model of persisting CD34+CD38- leukemic stem cells, we show that BMPR1B+ cells display co-activated Smad1/5/8 and Stat3 pathways. Interestingly, we reveal that only the BMPR1B+ cells adhering to stromal cells display a quiescent status. Surprisingly, this quiescence is induced by treatment, while non-adherent BMPR1B+ cells treated with tyrosine kinase inhibitors continued to proliferate. The subsequent targeting of BMPR1B and Jak2 pathways decreased quiescent leukemic stem cells by promoting their cell cycle re-entry and differentiation. Moreover, while Jak2-inhibitors alone increased BMP4 production by mesenchymal cells, the addition of the newly described BMPR1B inhibitor (E6201) impaired BMP4-mediated production by stromal cells. Altogether, our data demonstrate that targeting both BMPR1B and Jak2/Stat3 efficiently impacts persisting and dormant leukemic stem cells hidden in their bone marrow microenvironment.

scholarly journals Concurrent TP53 and CDKN2A Gene Aberrations in Newly Diagnosed Mantle Cell Lymphoma Correlate with Chemoresistance and Call for Innovative Upfront Therapy

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2120 ◽  
Author(s):  
Diana Malarikova ◽  
Adela Berkova ◽  
Ales Obr ◽  
Petra Blahovcova ◽  
Michael Svaton ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Kinase Inhibitor ◽  
Cell Lymphoma ◽  
Bone Marrow Involvement ◽  
B Cell Lymphoma ◽  
Prognostic Impact ◽  
Newly Diagnosed ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Mantle Cell ◽  
Reliable Marker

Mantle cell lymphoma (MCL) is a subtype of B-cell lymphoma with a large number of recurrent cytogenetic/molecular aberrations. Approximately 5–10% of patients do not respond to frontline immunochemotherapy. Despite many useful prognostic indexes, a reliable marker of chemoresistance is not available. We evaluated the prognostic impact of seven recurrent gene aberrations including tumor suppressor protein P53 (TP53) and cyclin dependent kinase inhibitor 2A (CDKN2A) in the cohort of 126 newly diagnosed consecutive MCL patients with bone marrow involvement ≥5% using fluorescent in-situ hybridization (FISH) and next-generation sequencing (NGS). In contrast to TP53, no pathologic mutations of CDKN2A were detected by NGS. CDKN2A deletions were found exclusively in the context of other gene aberrations suggesting it represents a later event (after translocation t(11;14) and aberrations of TP53, or ataxia telangiectasia mutated (ATM)). Concurrent deletion of CDKN2A and aberration of TP53 (deletion and/or mutation) represented the most significant predictor of short EFS (median 3 months) and OS (median 10 months). Concurrent aberration of TP53 and CDKN2A is a new, simple, and relevant index of chemoresistance in MCL. Patients with concurrent aberration of TP53 and CDKN2A should be offered innovative anti-lymphoma therapy and upfront consolidation with allogeneic stem cell transplantation.

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