scholarly journals Non-Classical Monocyte Abundance Is an Independent Adverse Risk Factor for Relapse in Pediatric B-ALL

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1316-1316
Author(s):  
Gloria Paz Contreras Yametti ◽  
Nikki Ann Evensen ◽  
Meenakshi Devidas ◽  
Elizabeth A. Raetz ◽  
Karen R Rabin ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Multivariable Analysis ◽  
Clinical Samples ◽  
Monocyte Subset ◽  
Long Term Treatment ◽  
Classical Monocytes

Abstract Background Acute Lymphoblastic Leukemia (ALL) is the most common pediatric cancer and while curable in the majority of cases, 15%-20% of children will relapse with only 50% surviving long-term. Treatment failures arise from the outgrowth of pre-existing or acquired sub-clones that are genetically or epigenetically primed to resist treatment. In addition, the bone marrow microenvironment is known to provide a protective niche. We performed the first mapping of the human B-cell ALL (B-ALL) immune bone marrow (BM) microenvironment at single cell resolution at diagnosis, remission and relapse (Witkowski, 2020). We uncovered a striking rewiring of the myeloid compartment during B-ALL progression with significant over-representation of a leukemia-associated monocyte subpopulation expressing high levels of the Macrophage Colony Stimulating Factor Receptor (M-CSFR/CSF1R). Using both peripheral blood (PB) complete blood count analysis and RNA-seq data, we demonstrated that high monocyte abundance at B-ALL diagnosis is predictive of inferior pediatric and adult overall survival in two large independent clinical cohorts. To determine the association of non-classical monocyte abundance in BM and PB with risk of relapse, we examined a cohort of clinical samples from children enrolled on Children's Oncology Group (COG) protocols. Methods Using an unmatched case-control design, we established a preliminary cohort of PB and BM samples collected at diagnosis from 24 B-ALL patients with eventual relapse and 24 patients in long-term remission. Four remission samples from an NYU Langone cohort were used to validate the expansion of this population in the presence of B-ALL. We applied a customized flow cytometry based assay to identify CD115-expressing human monocyte subsets: classical (CD45 +CD56 -CD14 +CD16 -), non-classical (CD45 +CD56 -CD14 -CD16 +), as well as B-cells (CD19, CD22, CD10) and T/NK cells (CD3, CD56). We then performed univariate and multivariable analysis of outcome (relapse versus long-term remission) compared to monocyte subset abundance, adjusting for potential confounding factors (age, gender, CNS status, NCI risk, genetic subtype, WBC at diagnosis, and end of induction minimal residual disease). Results We observed a significantly higher percentage of non-classical monocytes in the diagnostic BM from the COG cohort when compared to remission samples (COG diagnostic B-ALL BM non-classical percentage mean 52.19% vs NYU B-ALL remission BM non-classical percentage mean 1.775%, P = 0.0001). We also observed a strong correlation between the percentage of non-classical monocytes in the PB when compared to their matched BM specimens (r = 0.6, P = 0.0001). Multivariable analysis revealed a significant association between PB non-classical monocyte percentage at diagnosis and patient outcome (remission cohort non-classical monocyte percentage [mean, range]: 52.4%, 33.3-68.1%, n = 24, relapse cohort non-classical monocyte percentage: 65.9%, 56.4-84.7%, n = 24, P = 0.021). Similarly, a strong trend was observed in the BM, although it did not reach statistical significance. Flow cytometric analysis confirmed CD115 (M-CSFR/CSF1R) expression in this non-classical monocyte population, thereby validating a novel target for intervention. Conclusions These findings validate the presence of a unique monocyte subpopulation associated with childhood B-ALL and suggests that assessing this population in PB at diagnosis may be of prognostic significance. The availability of small molecule inhibitors and monoclonal antibodies targeting CSF1R-expressing monocytes may offer a novel approach to treating B-ALL. Figure 1 Figure 1. Disclosures Raetz: Pfizer: Research Funding; Celgene: Other: DSMB member. Teachey: Sobi: Consultancy; NeoImmune Tech: Research Funding; Janssen: Consultancy; BEAM Therapeutics: Consultancy, Research Funding. Aifantis: AstraZeneca: Research Funding; Foresite (FL2020-010) LLC: Consultancy.

scholarly journals Management of Cytopenias in CTLA4 Haploinsufficiency Using Abatacept and Sirolimus

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2409-2409 ◽  
Author(s):  
Gulbu Uzel ◽  
Djuro Karanovic ◽  
Hua Su ◽  
Amy Rump ◽  
Anahita Agharahimi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Adverse Events ◽  
Research Funding ◽  
Bone Marrow Failure ◽  
Critical Role ◽  
Lymphocytic Infiltration ◽  
Splenic Sequestration ◽  
Autoimmune Destruction ◽  
Long Term Treatment

Abstract Background: CTLA4 is a homodimeric cell surface inhibitory receptor that plays a critical role in maintaining immune system homeostasis by suppressing T-lymphocyte activation and proliferation. Heterozygous germline, loss-of-function mutations in CTLA4, present with a diverse clinical phenotype of recurrent infections, lymphoproliferation, autoimmunity, and lymphocytic infiltration of target organs. Cytopenias are common in CTLA4 Haploinsufficiency and can be often multifactorial due to autoimmune destruction, splenic sequestration and bone marrow failure.(Kuehn HS …. Uzel G. Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4.Science. 2014 Sep 26;345(6204):1623-1627. doi: 10.1126/science.1255904.) Patients and Methods: We have identified 95 CTLA4 mutation-positive subjects at the NIH CC, and a subset (n=74, 77%) of them exhibit symptomatic disease affecting brain, lungs, gut, spleen and bone marrow. Mean age for the affected cohort is 25 ± 2.0 years, and average age of onset of cytopenia is 16 years (range 6-43years). Of all patients with confirmed mutations, there are roughly equal numbers of females to males (1.15:1 ratio), but males dominate the affected cohort (69% males vs 31% females). Cytopenias due to autoimmune destruction, splenic sequestration and/or bone marrow failure with polyclonal lymphocytic infiltration are the most frequent initial presentation (59%; n=33): Thrombocytopenia (n=13), anemia (n=4), Evans' syndrome (n=7), and multilineage cytopenia (n=9). Splenomegaly is seen in 60% of the affected cohort. Results: We share our experience with short and long term immunomodulatory therapy in treating autoimmune cytopenias in 22 patients with CTLA4 deficiency,, including our experience with off-label use of the CTLA4 mimetic, abatacept(n=10), given at a dose of 500-750mg X2 as monthly intravenous infusions and sirolimus (n=19) with a target to maintain 24hr trough levels of 10-15ng/dL. The most frequent other concomitant immunomodulatory medication used was rituximab (n=10), azathioprine (n=5), mycophenolate mofetil (n=4), cyclosporine (n=3), hydroxychloroquine (n=1), ruxolitinib (n=1), mercaptopurine (n=1), and cyclophosphamide (n=1). Three patients received romiplostim and/or eltrombopag. All 22 patients received more than one course of pulse dose steroids. We have cumulative retrospective data of 17 patient-years in 10 CTLA4-deficient patients followed at NIH CC on abatacept. All of them showed either complete or partial response in terms stabilization of their cytopenias and/or improvement of their gastrointestinal symptoms and brain lesions. We did not observe any abatacept related adverse events: including infusion reactions, EBV reactivation, or diagnosis of malignancy. One patient died secondary to Klebsiella pneumoniae sepsis 3 months after stopping abatacept. His disease was complicated by large granular lymphocyte leukemia and treatment with alemtuzumab prior to his diagnosis with CTLA4 deficiency and abatacept treatment. Overall, we used mTOR inhibitors in 19 patients for a total of 37 patient years to treatment. Three most common recorded adverse events were: Clostridium difficile colitis (n=9, in 4 patients), lipid abnormalities (n =7, 3 patients required treatment) and bacterial pneumonia (n=6, in 4 patients). Conclusion: As abatacept replaces the missing CTLA4 protein, it should be part of the treatment regimen in patients with CTLA4 haploinsufficiency presenting with cytopenias. Both long term treatment outcomes and schedule of administration are yet to be determined in a larger cohort in the setting of a clinical trial. Disclosures Uzel: Novartis: Research Funding. Rao:novartis: Research Funding.

Outcomes of Children, Adolescents, and Young Adults with Acute Lymphoblastic Leukemia Based on Blast Genotype at Diagnosis: A Report from the Children's Oncology Group

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 451-451 ◽  
Author(s):  
Mignon L. Loh ◽  
Elizabeth Raetz ◽  
Meenakshi Devidas ◽  
Yunfeng Dai ◽  
Michael J. Borowitz ◽  
...  
Keyword(s):  
Risk Factors ◽  
Overall Survival ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Multivariable Analysis ◽  
Oncology Group ◽  
Genetic Groups ◽  
Independent Prognostic Significance ◽  
Independent Risk Factors

Abstract Survival for childhood acute lymphoblastic leukemia (ALL) now approaches 90% with risk adapted therapy based on National Cancer Institute risk group (NCI RG) at diagnosis, somatic lymphoblast genetics, and early response to therapy as measured by minimal residual disease (MRD). The Children's Oncology Group AALL03B1 ALL Classification trial enrolled 11,145 children, adolescents, and young adults less than 31 years of age with newly diagnosed B- or T-lineage ALL between December 2003 and September 2011. Companion therapeutic trials for B-lineage ALL included AALL0331 (n= 5226) for NCI standard risk (SR-ALL)(age 1-10 years and white blood cell count (WBC) < 50,000/uL) and AALL0232 (n=2907] for NCI high risk (HR) ALL (age > 10 years or presenting WBC > 50,000/uL). Assessing outcome by lymphoblast genetics revealed statistically significant distributions of genotype and NCI RG, as well as differences in event-free and overall-survival (EFS, OS) (Table 1). Not surprisingly, favorable genetic groups of Trisomy 4/10/17 (TT) and ETV6/RUNX1 were significantly more common in NCI SR patients (p< 0.0001 for each) while those with unfavorable characteristics (MLL rearranged [MLLr], intrachromosomal amplification of chromosome 21 [iAMP21], BCR/ABL1 and hypodiploidy [n<44]) occurred more frequently in NCI HR patients (p<0.0001 for each). Event-free and OS were correspondingly poorer in NCI HR patients with the exception of iAMP21, where EFS in those treated on AALL0232 was better than that in NCI SR (Table 1). Surprisingly, NCI SR BCR/ABL1 positive patients (N= 64, 1.2%) had a 5-year EFS of 85±5.0%, although these patients came off study at end induction and likely received imatinib with chemotherapy on a companion ALL trial for Ph+ ALL. Notably, hypodiploidy was associated with the worst EFS and OS regardless of NCI RG, with 5-year EFS and OS of 51.3±5.0% and 58.2±5.0%, respectively, suggesting that these patients continue to fare poorly with salvage therapies. Multivariable analysis demonstrated age, WBC, and day 29 MRD as significant independent risk factors for sustained CR, and the individual genetic groups of TT, ETV6/RUNX1, iAMP21, BCR/ABL1 and hypodiploidy, but notably, not MLLr, all retained independent prognostic significance when added to the model individually. A subset of consecutively enrolled (N=605) AALL0232 NCI HR patients underwent additional genomic interrogation, including assessment of Ph-like status, ABL1 class fusions, CRLF2r, JAK mutations (JAKm), and IKZF1 alterations. Based on sample availability, patients studied were younger (p < 0.0001) and had a higher WBC (p < 0.0001) compared to the remainder of AALL0232. There were 85/605 (14.0%) Ph-like patients defined using PAM clustering algorithms and Ph-like status was significantly associated with an IKZF1 alteration (75%) (p < 0.0001) and day 29 MRD > .01% (p < 0.0001). Five-year EFS for Ph-like versus non Ph-like was 62.3±5.8% vs. 83.9±1.7% (p < 0.0001). Outcomes of Ph-like ALL with or without CRLF2r were similar (60.6±8.3% versus 65.4±8.0%, p =0.86). Similarly, 5-year EFS of Ph-like ALL was no different with or without IKZF1 alterations (61.5±7.0% vs. 64.6 ±11.1%). There were 155 (27.1%) IKZF1 alterations, 60 of which occurred in Ph-like ALL with a trend towards concomitant CRLF2r/JAKm (p=0.055). Five-year EFS for patients with IKZF1 alterations was 66.8±4.0% (p < 0.0001) versus 86.4±1.8% for those without IKZF1 lesions. Multivariable analysis demonstrated age, WBC and day 29 MRD as independent risk factors for sustained CR while only Ph-like status, IKZF1 alteration, BCR/ABL1 and ETV6/RUNX1retained independent prognostic significance when added to the model individually. In summary, somatic sentinel cytogenetic alterations are independently prognostic in childhood ALL and are strongly associated with NCI RG and outcome, supporting continued incorporation into risk stratification algorithms. Notably, >44% of all patients have favorable blast cytogenetics with 5-year overall survival rates approaching 100%. In contrast, NCI HR patients with Ph-like ALL have poor outcomes with currently available therapy and this subtype is associated with CRLF2 r and IKZF1 alterations, which do not confer an inferior EFS within the Ph-like subgroup. Novel therapies for genomicallydefined Ph-like ALL may improve outcomes. Disclosures Loh: Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding. Borowitz:HTG Molecular: Consultancy; Bristol-Myers Squibb: Research Funding; MedImmune: Research Funding; BD Biosciences: Research Funding.

Early Response Characteristics and Blast Cytogenetic FEatures In 5,377 Children with Standard Risk Acute Lymphoblastic Leukemia (SR-ALL): A Children's Oncology Group (COG) Study

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 414-414
Author(s):  
Kelly W. Maloney ◽  
Mignon L. Loh ◽  
Elizabeth Raetz ◽  
Michael J. Borowitz ◽  
Meenakshi Devidas ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Induction Therapy ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Philadelphia Chromosome ◽  
Early Response ◽  
Response To Therapy ◽  
Intrathecal Therapy ◽  
Post Induction

Abstract Abstract 414 The COG uses clinical characteristics, blast cytogenetic features and early response to therapy, as measured by bone marrow (BM) morphology on days 8, 15 and 29 and BM minimal residual disease (MRD) measured by flow cytometry in one of two central COG reference laboratories on day 29 of induction in order to modulate the intensity of post-induction therapy for children with ALL. A slow early response (SER) to therapy was defined by M2/M3 BM on day 15 or MRD ≥ 0.1% on day 29. The COG AALL0331 trial accrued 5377 children with NCI SR- ALL (age 1–10 years with an initial white blood cell count of <50,000/microliter) between 4/11/2005 and 5/28/2010. Induction therapy consisted of dexamethasone (6mg/m2/day × 28 days), PEG asparaginase (2500 units/m2 × 1), vincristine (1.5 mg/m2 weekly × 4) and intrathecal therapy (cytarabine on day 0 and methotrexate on days 8 and 29) according to age based dosing. Those patients with a day 29 M2 BM (5–25% blasts) or MRD ≥1% received two additional weeks of induction therapy using the same agents with one added dose of daunorubicin (25 mg/m2). Children with an M3 marrow (>25% blasts) on day 29, or an M2 marrow or MRD ≥1% on day 43 after 2 weeks of extended induction therapy were classified as induction failures. Following the first month of therapy, patients were assigned to different risk groups for post-induction therapy. We examined the correlations between clinical features, leukemic blast cytogenetic features (favorable: ETV6-RUNX1 and trisomies 4, 10, and 17 or unfavorable: MLL rearrangements, BCR-ABL1 and hypodiploidy), and response to induction therapy. MRD at end induction was ≥ 0.1% more frequently in patients with the absence of either ETV6-RUNX1 (10.4% vs. 3.5%, P<0.0001) or trisomies 4, 10, and 17 (TT) (9.5% vs 5.9%, p=0.0001) or among those who harbored MLL rearrangements (26.1% vs. 8.5%, p=0.0004). MRD > 0.1% at end induction was seen in 23.3% of hypodiploid patients and 32.4% of Philadelphia chromosome + or BCR-ABL1 + patients. In addition, those who had an M2/M3 marrow at day 15 (36.7% vs. 5.9%, p <0.0001) were more likely to have MRD ≥ 0.1% at end induction. There was no difference in the proportion of boys and girls with MRD ≥0.1% (8.5% vs. 8.1%). Only 114/5082 (2.2%) children received extended induction. Induction failures were rare, occurring in only 37/5075 (0.7%) of patients. Induction failures defined by an M3 marrow on day 29 occurred in 6/5123 patients, while induction failures at day 43 after extended induction, occurred in 31/5067 (0.61%) patients (day 43 M2 marrow: 2, day 43 MRD ≥1%: 29). (see Table 1). Conclusions: Inferior MRD responses were associated with the absence of favorable blast cytogenetics and slow initial responses (M2/3 marrow) on day 15 of induction consistent with the known prognostic significance of these variables. Overall, NCI SR patients on AALL0331 had a very low incidence of induction failures, as measured either by bone marrow morphology or by MRD≥1% at day 43. However, the use of MRD identified additional patients who had a suboptimal response to induction, allowing for early augmentation of therapy. Disclosures: Borowitz: genzyme: Research Funding; becton-dickinson: Research Funding; Alexion: Consultancy; beckman-coulter: Research Funding. Mattano:pfizer: Employment.

LowERGandBAALCExpression Identifies a New Subgroup of Adult Acute T-Lymphoblastic Leukemia With a Highly Favorable Outcome

2007 ◽  
Vol 25 (24) ◽  
pp. 3739-3745 ◽  
Author(s):  
Claudia D. Baldus ◽  
Peter Martus ◽  
Thomas Burmeister ◽  
Stefan Schwartz ◽  
Nicola Gökbuget ◽  
...  
Keyword(s):  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Multivariable Analysis ◽  
Favorable Outcome ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Free Survival ◽  
Polymerase Chain ◽  
Low Expression

PurposeExpression of the genes ERG (v-ets erythroblastosis virus E26 oncogene homolog) and BAALC (brain and acute leukemia, cytoplasmic) shows similarity during hematopoietic maturation and predicts outcome in acute myeloid leukemia. We hypothesized that like ERG, BAALC expression might be of prognostic significance in acute T-lymphoblastic leukemia (T-ALL) and that ERG and BAALC expression together would better identify the patient's risk profile.Patients and MethodsERG and BAALC mRNA expression were determined by real-time reverse transcriptase polymerase chain reaction in 153 adults with T-ALL. Patients were designated low or high ERG expressers and low or high BAALC expressers.ResultsHigh BAALC expression correlated with a higher frequency of early T-ALL (P < .0001), CD34 positivity (P < .0001), coexpression of myeloid markers (P = .0001), and high ERG expression (P = .03). High BAALC compared with low BAALC patients had an inferior relapse-free survival (RFS; P = .0008) and overall survival (OS; P = .0001). In contrast, patients with low expression of both ERG and BAALC (representing 41% of all T-ALL patients) had the most favorable outcome (P < .0001; 4-year RFS: low ERG/low BAALC 81%; P < .0001; 4-year OS: low ERG/low BAALC 69%). On multivariable analysis, low ERG/low BAALC expression was of independent favorable prognostic significance (RFS, P = .001; OS, P = .003).ConclusionLow expression of both ERG and BAALC identifies T-ALL patients with a distinctly favorable long-term outcome.

scholarly journals Long-Term Sustained Responses Following Ibrutinib Discontinuation after Frontline Therapy with Obinutuzumab Plus Ibrutinib in Patients with Chronic Lymphocytic Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 33-34
Author(s):  
Paula A. Lengerke Diaz ◽  
Michael Y. Choi ◽  
Eider F. Moreno Cortes ◽  
Jose V. Forero ◽  
Juliana Velez-Lujan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Side Effects ◽  
Chronic Lymphocytic Leukemia ◽  
Disease Progression ◽  
Research Funding ◽  
Lymphocytic Leukemia ◽  
Combination Regimen ◽  
Grade 3

Single oral targeted therapies have emerged as a standard of care in chronic lymphocytic leukemia (CLL). However, accessibility, side effects, and financial burden associated with long term administration limit their clinical use. Mainly, it is unclear in what clinical situation discontinuation of oral therapy can be recommended. The combination of type II anti-CD20 antibody obinutuzumab-Gazyva® with ibrutinib (GI) has shown a significant progression-free survival benefit in patients (pts) with CLL, including those with high-risk genomic aberrations. We conducted a phase 1b/2, single-arm, open-label trial to evaluate the safety and efficacy of GI as first-line treatment in 32 CLL pts. We report the outcome in pts that discontinued ibrutinib (either after 3 years of sustained complete response (CR) as stipulated in the clinical protocol, or due to other reasons). CLL pts enrolled in this protocol were ≥65 years old, or unfit/unwilling to receive chemotherapy. Pts received GI for six cycles, followed by daily single-agent ibrutinib. The protocol was designed to ensure that pts with a sustained CR after 36 months were allowed to discontinue ibrutinib. The median age was 66 years (IQR 59-73), and 6% of the evaluated pts had 17p deletion. All pts were able to complete the six planned cycles of obinutuzumab. The combination regimen was well-tolerated, and the most common adverse events (&gt;5% CTCAE grade 3-4) were neutropenia, thrombocytopenia, and hyperglycemia. The rate and severity of infusion-related reactions (IRR) were much lower than expected (Grade≥ 3, 3%), and pts without IRR had lower serum levels of cytokines/chemokines CCL3 (P=0.0460), IFN-γ (P=0.0457), and TNF-α (P=0.0032) after infusion. The overall response rate was 100%, with nine pts (28%) achieving a CR, and four pts (12.5%) with undetectable minimal residual disease (uMRD) in the bone marrow, defined as &lt;10-4 CLL cells on multicolor flow cytometry. At a median follow-up of 35.5 months (IQR 24.5-42.7) after starting treatment, 91% of the enrolled pts remain in remission with a 100% overall survival. Sixteen pts have completed a long-term follow-up of 36 months. Six pts showed CR, with three of them achieving uMRD in the bone marrow. Ten of these pts were in PR, and only one had disease progression and started treatment for symptomatic stage I disease with obinutuzumab plus venetoclax. In total, thirteen pts (41%) have stopped ibrutinib, with a median time on treatment prior to discontinuation of 35 months. Five (16%) of these pts had CRs and discontinued after 36 months. Eight additional pts (25%) had PRs and discontinued ibrutinib without being eligible: three pts discontinued prior to 36 months due to toxicities, and five pts discontinued after 36 months (3 due to side effects, and 2 due to financially driven decision). One patient eligible to discontinue ibrutinib, decided to remain on treatment despite sustained CR. After a median follow up time following ibrutinib discontinuation of 8 months (IQR 3.5-17), only two out of 13 pts have progressed (10 and 17 months after Ibrutinib discontinuation). None of the pts that stopped ibrutinib after achieving a CR have shown signs of disease progression. Of note, the pharmaceutical sponsor provided ibrutinib for the first 36 months, after which pts or their insurer became financially responsible. This particular scenario could bias the discontinuation pattern compared to a real world experience. It also provided us with a perspective about diverse factors affecting the treatment choices of pts. In summary, the obinutuzumab plus ibrutinib combination therapy was well-tolerated, with a much lower IRR rate. Efficacy compares favorably with historical controls with all pts responding to therapy, no deaths associated with treatment or disease progression, and a longer than expected time-to-progression after discontinuation of ibrutinib. The rate of ibrutinib discontinuation was higher than reported in the literature, most likely influenced by the protocol design and financial decisions driven by the switch from sponsor-provided ibrutinib to insurance or self-paid medication. Our observations regarding safety, efficacy and lack of disease progression after ibrutinib discontinuation are encouraging, and warrant confirmation in long-term prospective studies. Clinicaltrials.gov Identifier NCT02315768. Funding: Pharmacyclics LLC. Disclosures Choi: AbbVie: Consultancy, Speakers Bureau. Amaya-Chanaga:AbbVie: Ended employment in the past 24 months, Other: Research performed while employed as an investigator of this study at UCSD.. Kipps:Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Castro:Kite Pharma: Research Funding; Pharmacyclics: Research Funding; Fate Therapeutics: Research Funding.

scholarly journals The Necessary for Long-Term Follow-up of Mutated Genes and Clonal Evolutions in Multiple Myeloma Combined with cfDNA Assay

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5515-5515
Author(s):  
Yuko Mishima ◽  
Yuji Mishima ◽  
Masahiro Yokoyama ◽  
Noriko Nishimura ◽  
Yoshiharu Kusano ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Genomic Dna ◽  
Research Funding ◽  
Somatic Mutations ◽  
Clinical Course ◽  
Bone Marrow Aspiration ◽  
Long Term Follow Up

Introduction)Somatic mutations in multiple myeloma (MM) are strongly related to the clinical outcome and clonal evolution over the clinical course, and are a major problem. From a clinical viewpoint, although numerous novel drugs have been utilized, achieving long-lasting and complete remission remains difficult. Recent studies have elucidated the mutated genes using next-generation sequencing, and have examined how clonal change can be acquired in myeloma. In this study, we traced the transition of the somatic mutations of bone marrow tumor cells in patients with MM over a long-term follow-up. Furthermore, we compared the somatic mutations found in serum cell-free DNA (cfDNA) and mutated genes obtained from bone marrow myeloma cells. Material and Methods)Patients diagnosed with multiple myeloma who provided written informed consent to participate in the study were enrolled. Patients were treated by immuno-chemotherapy with or without radiation between 2000 and 2017 at our institute. Bone marrow aspiration and biopsy were performed at the time of diagnosis and upon disease progression. Around the time of bone marrow aspiration, serum was obtained from a peripheral blood sample for cfDNA analysis. Myeloma cells were separated from bone marrow samples with MicroBeads of CD138 antibody and genomic DNA was extracted. The peripheral blood samples derived from myeloma patients. The cfDNA was extracted from the serum using a Maxwell RSC cfDNA Plasma kit. Using genomic DNA derived from cfDNA and bone marrow, multiplex polymerase chain reaction (PCR) was performed, and a sequence library was then constructed with an Ion Custom Amplicon panel. The panel for the sequence library was designed using an Ion AmpliSeq DesignerTM. 126 targeted genes were selected. The genomes were sequenced using the Ion ProtonTM System. This protocol was approved by the institutional review board and the Genomic Review Board of the Japanese Foundation for Cancer Research. Result)We followed 7 patients' long term-clinical course and the transition of mutations (8.5 year average). The expression of myeloma driver genes, such as RAS, BRAF, and MYC, were not critical. We did, however, detect a relationship between an increase in the dominant mutated gene, such as TP53, DIS3, FAM46C, KDM6B, and EGR1 and poor prognosis in patients with myeloma. Next, we calculated the cfDNA concentrations from 34 cases. The cfDNA concentrations were significantly higher than 10 control cases (average 62.0 ng/mL (0-200 ng/mL) and 8.18 ng/mL (4.3-14.1 ng/mL), P=0.0046). The 2.5 year-progression free survival (PFS) during the first treatment of MM were tend to be poorer in the group with cfDNA>50 ng/mL (72.9%) than the group with cfDNA<50 ng/mL(25.9%), however there are no statistical significance (P = 0.15).We caluculated concordance rate of derived mutations from bone marrow MM cells and cfDNA in 7 cases. The somatic mutations found in serum cell-free DNA (cfDNA) and bone marrow MM cells were determined the correlation coefficients. However, there are few difference expression pattern in each source. In cfDNA assay, CREEP, EGR1, HDAC4, HDAC6, and JMJD1C were highly expressed as 57.1% (4/7) - 85.7% (6/7), and these results were almost the same as those for bone marrow MM cells. On the other hand, KDM1A (85.7%), PI3KCD (71.4%), and KDM3B (57.1%) were highly detected in cfDNA, although those were not frequently expressed in bone marrow. Discussion)Our data demonstrate the importance of the long-term follow-up of somatic mutations during the clinical course of myeloma. Serum cfDNA is a useful alternative source for detecting somatic mutations in MM patients during long-term follow-up. Disclosures Mishima: Chugai-Roche Pharmaceuticals Co.,Ltd.: Consultancy. Yokoyama:Chugai-Roche Pharmaceuticals Co.,Ltd.: Consultancy. Nishimura:Chugai-Roche Pharmaceuticals Co.,Ltd.: Consultancy; Celgene K.K.: Honoraria. Hatake:Celgene K.K.: Research Funding; Janssen Pharmaceutical K.K.: Research Funding; Takeda Pharmaceutical Co.,Ltd.: Honoraria. Terui:Bristol-Myers Squibb K.K.: Research Funding; Bristol-Myers Squibb, Celgene, Janssen, Takeda, MSD, Eisai, Ono, and Chugai-Roche Pharmaceuticals Co.,Ltd.: Honoraria.

scholarly journals TEL-AML1 Fusion Transcript in Relapsed Childhood Acute Lymphoblastic Leukemia

Blood ◽  
1998 ◽  
Vol 91 (5) ◽  
pp. 1716-1722 ◽  
Author(s):  
Karlheinz Seeger ◽  
Hans-Peter Adams ◽  
Dirk Buchwald ◽  
Birgit Beyermann ◽  
Bernhard Kremens ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Philadelphia Chromosome ◽  
Fusion Transcript ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Long Term Results ◽  
Childhood All ◽  
Cryptic Translocation

Abstract The cryptic translocation t(12;21)(p13;q22) has been recently recognized as the most common genetic rearrangement in B-lineage childhood acute lymphoblastic leukemia (ALL). The resulting fusion transcript, termed TEL-AML1, has been associated with an excellent prognosis at initial ALL diagnosis. Hence, we postulated that the incidence of TEL-AML1 fusion should be lower in patients with ALL relapse. To address this assumption and to investigate the prognostic significance of TEL-AML1 expression in relapsed childhood ALL, bone marrow samples of 146 children were analyzed by reverse-transcriptase (RT)-polymerase chain reaction (PCR). All children were treated according to Berlin-Frankfurt-Münster (BFM) ALL relapse trial protocols (ALL-REZ BFM 90-96). Their clinical features and outcome were compared with those of 262 patients who could not be tested due to lack of bone marrow samples. Thirty-two of 146 children with relapsed ALL were TEL-AML1–positive. Four of the negative patients had T-lineage and nine Philadelphia chromosome (Ph1)-positive leukemia. Thus, the incidence ofTEL-AML1 in relapsed Ph1-negative, B-cell precursor ALL is 32 of 133 (24%). The 32 TEL-AML1–positive and 101 negative patients differed significantly with respect to duration of last remission (42.5 v 27 months; P = .0001) and age at initial diagnosis (53.5 v 74 months;P = .0269). At a median follow-up time of 21.5 months, children positive for TEL-AML1 had a significantly (P = .0011) higher probability of event-free survival (EFS; 0.79 v 0.33). The predominant majority of patients had been treated for initial ALL according to German multicenter BFM (108 of 133) or Cooperative ALL study group (CoALL) (19 of 133) frontline protocols. The comparison of tested and not-tested (N = 262) patients showed no significant difference.TEL-AML1 positivity predicted a favorable short-term outcome; long-term results are unknown. Screening for TEL-AML1 should become routine at relapse diagnosis and might be used for therapy stratification in future trials.

scholarly journals Sustained long-term hematopoiesis after myeloablative therapy with peripheral blood progenitor cell support

Blood ◽  
1995 ◽  
Vol 85 (12) ◽  
pp. 3754-3761 ◽  
Author(s):  
R Haas ◽  
B Witt ◽  
R Mohle ◽  
H Goldschmidt ◽  
S Hohaus ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Peripheral Blood ◽  
Progenitor Cell ◽  
Lymphoblastic Leukemia ◽  
Peripheral Blood Progenitor Cell ◽  
Myelogenous Leukemia ◽  
High Dose ◽  
Platelet Recovery ◽  
Cd34 Cells

A retrospective analysis of long-term hematopoiesis was performed in a group of 145 consecutive patients who had received high-dose therapy with peripheral blood progenitor cell (PBPC) support between May 1985 and December 1993. Twenty-two patients had acute myelogenous leukemia, nine had acute lymphoblastic leukemia, 43 had Hodgkin's disease, 57 had non- Hodgkin's lymphoma, and 14 patients had multiple myeloma. Eighty-four patients were male and 61 female, with a median age of 37 years (range, 16 to 58 years). In 46 patients, PBPC were collected after cytotoxic chemotherapy alone, while 99 patients received cytokines either during steady-state hematopoiesis or post-chemotherapy. Sixty patients were treated with dose-escalated polychemotherapy, and 85 patients had a conditioning therapy including hyperfractionated total body irradiation at a total dose of 14.4 Gy. The duration of severe pancytopenia posttransplantation was inversely related to the number of reinfused granulocyte-macrophage colony-forming units (CFU-GM) and CD34+ cells. Threshold quantities of 2.5 x 10(6) CD34+ cells per kilogram or 12.0 x 10(4) CFU-GM per kilogram became evident and were associated with rapid neutrophil and platelet recovery within less than 18 and 14 days, respectively. These numbers were also predictive for long-term reconstitution, indicating that normal blood counts are likely to be achieved within less than 10 months after transplantation. Conversely, 12 patients were autografted with a median of 1.75 x 10(4) CFU-GM per kilogram resulting in delayed recovery to platelet counts of greater than 150 x 10(9)/L between 1 and 6 years. Our study includes bone marrow examinations in 50 patients performed at a median follow-up time of 10 months (range, 1 to 85 months) posttransplantation. A comparison with normal volunteers showed a 3.2-fold smaller proportion of bone marrow CD34+ cells, which was paralleled by an even more pronounced reduction in the plating efficiency of CFU-GM and burst-forming unit-erythroid. No secondary graft failure was observed, even in patients autografted with relatively low numbers of progenitor cells. This suggests that either the pretransplant regimens were not myeloablative, allowing autochthonous recovery, or that a small number of cells capable of perpetual self-renewal were included in the autograft products.

Allogeneic bone marrow transplantation for children with acute lymphoblastic leukemia in first remission: a cooperative study of the Groupe d'Etude de la Greffe de Moelle Osseuse.

1989 ◽  
Vol 7 (6) ◽  
pp. 747-753 ◽  
Author(s):  
P Bordigoni ◽  
J P Vernant ◽  
G Souillet ◽  
E Gluckman ◽  
D Marininchi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Bone Marrow Transplantation ◽  
Lymphoblastic Leukemia ◽  
Allogeneic Bone Marrow Transplantation ◽  
Disease Free Survival ◽  
Allogeneic Bone ◽  
Free Survival ◽  
Disease Free

Thirty-two children ranging in age from 1.5 to 16 years with poor-prognosis acute lymphoblastic leukemia (ALL) were treated with myeloablative immunosuppressive therapy consisting of cyclophosphamide (CPM) and total body irradiation (TBI) followed by allogeneic bone marrow transplantation (BMT) while in first complete remission (CR). The main reasons for assignment to BMT were WBC count greater than 100,000/microL, structural chromosomal abnormalities, and resistance to initial induction therapy. All children were transplanted with marrow from histocompatible siblings. Twenty-seven patients are alive in first CR for 7 to 82 months post-transplantation (median, 30 months). The actuarial disease-free survival rate is 84.4% (confidence interval, 7.2% to 29%) and the actuarial relapse rate is 3.5% (confidence interval, 0.9% to 13%). Four patients died of transplant-related complications, 16 developed low-grade acute graft-v-host disease (GVHD), and six developed chronic GVHD. The very low incidence of relapse (one of 28 long-term survivors) precluded the determination of the prognostic significance of the different poor-outcome features. Moreover, two infants treated with busulfan, CPM, and cytarabine (Ara-C) relapsed promptly in the marrow. In summary, as a means of providing long-term disease-free survival and possible cure, BMT should be considered for children with ALL presenting poor-prognostic features, particularly certain chromosomal translocations [t(4;11), t(9;22)], very high WBC counts, notably if associated with a non-T immunophenotype, and, perhaps, a poor response to initial therapy with corticosteroids (CS), or infants less than 6 months of age.

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