Mixed phenotype acute leukemia (MPAL) is a rare type of acute leukemia with immunophenotypic features of both myeloid-derived and lymphoid-derived lineages.
We present an atypical case of a ...32-year-old woman presenting with an anterior mediastinal mass and pericardial/pleural involvement that was initially diagnosed as primary mediastinal diffuse large B-cell lymphoma. However, flow cytometry on pleural fluid confirmed the diagnosis of MPAL of B-cell/myeloid lineage without peripheral blood/bone marrow involvement. The patient was treated with an acute lymphoblastic leukemia-type regimen and proceeded with myeloablative allogeneic hematopoietic cell transplantation in first complete remission.
MPAL can rarely present with isolated extramedullary disease without leukemic involvement and can often be misdiagnosed as a non-Hodgkin lymphoma. Careful integration of all the clinical data, particularly flow cytometry results, can clarify the diagnosis and change the treatment plan.
Highlights • Contemporary data on outcomes of allogeneic hematopoietic cell transplant (HCT) for T-cell acute lymphoblastic leukemia (T-ALL) are limited. • Overall survival after HCT at 5 years for ...T- ALL was 34%. The corresponding cumulative incidence of non-relapse mortality and relapse was 26% and 41% respectively. • In multivariable analysis, factors significantly associated with overall survival were the use of TBI (HR 0.57, P=0.02); age >35 (HR 1.55, P=0.025), and relapsed/refractory disease status at transplantation (HR 1.98, P=0.005). • Allogeneic HCT remains a potentially curative option in selected patients with T-ALL, however relapse remains the major cause of treatment failure.
Summary
Aminotransferases can be redundant or promiscuous, but the extent and significance of these properties is not known in any organism, even in Escherichia coli. To determine the extent of ...redundancy, it was first necessary to identify the redundant aminotransferases in arginine and lysine synthesis, and then complement all aminotransferase‐deficient mutants with genes for all aminotransferases. The enzymes with N‐acetylornithine aminotransferase (ACOAT) activity in arginine synthesis were ArgD, AstC, GabT and PuuE; the major anaerobic ACOAT was ArgD. The major enzymes with N‐succinyl‐l,l‐diaminopimelate aminotransferase (SDAP‐AT) activity in lysine synthesis were ArgD, AstC, and SerC. Seven other aminotransferases, when overproduced, complemented the defect in a triple mutant. Lysine availability did not regulate synthesis of the major SDAP‐ATs. Complementation analysis of mutants lacking aminotransferases showed that the SDAP‐ATs and alanine aminotransferases were exceptionally redundant, and it is proposed that this redundancy may ensure peptidoglycan synthesis. An overview of all aminotransferase reactions indicates that redundancy and broad specificity are common properties of aminotransferases.
Introduction The challenges posed by the increasing incidence of hematologic malignancies in older patients are significant and while during the past 20 years there has been a dramatic expansion in ...the therapeutic armamentarium against hematologic malignancies, there is a need for data to guide treatment decisions for older adults, particularly with respect to the use of novel targeted or immunotherapeutic agents. To a large extent, this is a consequence of the under-representation of this growing demographic in cancer-related clinical trials.
Management of primary CNS lymphoma (PCNSL) in patients age ≥ 70 years represents a significant problem. While it is established that older PCNSL patients benefit from high-dose methotrexate-based induction regimens, whole brain irradiation consolidation is not a favored option because of excessive neurotoxicity. While there is evidence that high‐dose chemotherapy improves outcomes in patients age < 70, dose‐intensive chemotherapy is not an option for most older PCNSL patients. Given that the median age of PCNSL at diagnosis is ~ 60 years, determination of the optimal consolidative approach for older patients is an important question. This problem is particularly significant given that the incidence of PCNSL continues to rise in this older age group.
While PCNSL increasingly appears to be a curable brain tumor, outcomes for patients age > 60 remain poor, with 1-year progression-free survival (PFS) of ~ 40% and median overall survival of 14-30 months. Population-based registry data suggests a median overall survival for PCNSL patients age > 70 of approximately 7 months over the past decade. New therapeutic approaches are needed for the particularly vulnerable older PCNSL patient population.
Given the evidence for activity of low-dose lenalidomide in relapsed primary and secondary CNS lymphoma, in 2011, we began using low-dose lenalidomide as maintenance in consecutive older PCNSL patients (age ≥ 70 years, HIV negative) following standard methotrexate/rituximab-based induction, in lieu of surveillance, whole brain irradiation or high-dose chemotherapeutic consolidation. Here we report on the characteristics, outcomes, toxicities, progression-free and overall survival of the first 11 PCNSL patients, age ≥ 70, to receive lenalidomide maintenance after high-dose methotrexate-based induction at our institution.
Results Eleven patients age > 70 received low-dose lenalidomide maintenance 5-10 mg/d on a 21-d cycle after induction therapy for PCNSL.Median age of the cohort is 77 years (range 70-86). Median Karnofsky performance status (KPS) is 60 (range 50-80); median IELSG prognostic risk score is 4 (range 3-5). The median methotrexate dose administered was 2.5 grams/m2 (range 0.5 - 8). With overall median follow-up of 30 months, median time on lenalidomide maintenance is 14.8 months (range 0.9 - 65.2). Two patients received lenalidomide plus maintenance rituximab, every 6 months. Median PFS is 48 months (range 16.8 - 84.8). Median OS has not been reached, and there have been no deaths (Figure 1). Four patients experienced disease progression on lenalidomide; 3 of them continued maintenance lenalidomide after salvage and 1 received maintenance pomalidomide. Lenalidomide maintenance has generally been well-tolerated. However, 5 toxicities potentially related to therapy have mandated cessation of lenalidomide: 1 grade 2 arthralgia, 1 subdural hematoma, 1 pneumonia, 1 grade 3 fatigue, 1 deep vein thrombosis.
Conclusions These encouraging preliminary results of prolonged PFS and OS with low-dose lenalidomide illustrate the feasibility and challenges, as well as suggest a potential benefit of maintenance therapy with low-dose lenalidomide in older patients with PCNSL. Nine of 11 patients were able to complete at least 8 months of lenalidomide maintenance after induction therapy. Toxicities were manageable and strikingly, there have been no deaths. Recently, lenalidomide has been shown to enhance the proliferation, survival, and chemotactic responses in T-cells isolated from older subjects. This suggests a potential mechanistic basis by which low-dose lenalidomide may improve immunity in the elderly and potentiate response to chemotherapy. Future studies are needed to prospectively test the benefit and mechanisms of lenalidomide maintenance in older patients with PCNSL.
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Rubenstein:Genentech: Research Funding; Celgene: Research Funding. Mannis:AbbVie: Membership on an entity's Board of Directors or advisory committees; Agios: Research Funding; NKarta: Membership on an entity's Board of Directors or advisory committees.
The histone deacetylase (HDAC) inhibitor romidepsin and the anthracycline liposomal doxorubicin (LD) have modest single-agent activity in cutaneous T-cell lymphoma (CTCL) and peripheral T-cell ...lymphoma (PTCL). We investigated the safety and efficacy of the combination of these two agents in CTCL and PTCL.
Using CTCL cell lines and primary CTCL tumor cells, we demonstrated synergistic antitumor activity with romidepsin plus doxorubicin. We then conducted a phase I dose-escalation study of the romidepsin/LD combination in relapsed/refractory CTCL and PTCL. The primary objective was to determine the MTD of romidepsin in combination with LD at 20 mg/m
i.v., once every 28 days.
Eleven patients with CTCL and 12 patients with PTCL were treated. The MTD of romidepsin was determined to be 12 mg/m
. Grade 3/4 hematologic toxicities included thrombocytopenia (17%), anemia (13%), and neutropenia (9%). The most frequent treatment-related nonhematologic adverse events were fatigue (48%), nausea (48%), vomiting (35%), and anorexia (30%). Among 21 evaluable patients, the overall response rate was 70% 1 complete response (CR), 6 partial responses (PR) in CTCL and 27% (3 CR, 0 PR) in PTCL. Of the patients with CTCL, 8 of 10 had skin response, including 6 patients (60%) achieving skin involvement less than 10% of their body surface area at time of best response.
Romidepsin plus LD demonstrated an acceptable safety profile and promising clinical efficacy with deep skin responses in relapsed/refractory CTCL. Thus, this combination could be considered as a bridge to skin-directed treatment or allogeneic hematopoietic cell transplantation in patients with aggressive CTCL.
Summary
Aminotransferases can be redundant or promiscuous, but the extent and significance of these properties is not known in any organism, even in
E
scherichia coli
. To determine the extent of ...redundancy, it was first necessary to identify the redundant aminotransferases in arginine and lysine synthesis, and then complement all aminotransferase‐deficient mutants with genes for all aminotransferases. The enzymes with
N
‐acetylornithine aminotransferase (
ACOAT
) activity in arginine synthesis were
ArgD
,
AstC
,
GabT
and
PuuE
; the major anaerobic
ACOAT
was
ArgD
. The major enzymes with
N
‐succinyl‐
l
,
l
‐diaminopimelate aminotransferase (
SDAP
‐
AT
) activity in lysine synthesis were
ArgD
,
AstC
, and
SerC
. Seven other aminotransferases, when overproduced, complemented the defect in a triple mutant. Lysine availability did not regulate synthesis of the major
SDAP
‐
ATs
. Complementation analysis of mutants lacking aminotransferases showed that the
SDAP
‐
ATs
and alanine aminotransferases were exceptionally redundant, and it is proposed that this redundancy may ensure peptidoglycan synthesis. An overview of all aminotransferase reactions indicates that redundancy and broad specificity are common properties of aminotransferases.
Introduction: Axicabtagene Ciloleucel (axi-cel), a CD19 chimeric antigen receptor (CAR) T-cell therapy, was approved for the treatment of relapsed/refractory aggressive B-cell non-Hodgkin lymphoma in ...October, 2017. In the ZUMA-1 trial leading to axi-cel FDA approval, patients (pts) with prior or active secondary central nervous system (CNS) lymphoma involvement were excluded. A recent publication of 8 pts with secondary CNS lymphoma who underwent Tisagenlecleucel CAR T cell therapy was reported (Frigault M.J.2019). Since the two FDA approved CAR T cell products have a different neurotoxicity profile, understanding outcomes of axi-cel in this setting is important. We report here the real-world experience of 17 pts treated with axi-cel who had a history of secondary CNS involvement or had active CNS disease at time of CAR T infusion.
Methods: Seventeen academic centers from the US Lymphoma CAR T Consortium contributed data independently from the manufacturer. Data regarding secondary CNS involvement, management, and outcome were obtained in addition to CAR T therapy outcome for pts who were identified as having active, secondary CNS involvement at the time of evaluation for CAR-T therapy. Nine centers reported data on 17 cases with CNS involvement. Follow-up data was missing for one pt in the CNS cohort. Lee criteria or the modified Lee grading scale were used for cytokine release syndrome (CRS). CTCAEv4 or CARTOX grading were used for immune effector cells associated neurotoxicity syndrome (ICANS). All leukapheresed pts were included in the intention to treat (ITT) analysis for response rate and event-free survival (EFS). EFS was defined as date of leukapheresis until progression or death due to any cause. EFS was evaluated using Kaplan Meier curves with log-rank test. Differences in clinical characteristics and response between CNS and non-CNS pts were not formally tested due to small sample size and multiple comparison concerns.
Results: With a data cut-off of 4/30/2019, 300 pts underwent leukapheresis with intention to manufacture standard of care axi-cel. By the time of leukapheresis, 17 (6%) had secondary CNS involvement (4 parenchymal disease, 10 leptomeningeal/CSF, 3 data not available). Compared to the non-CNS cohort, baseline demographics were comparable (Panel A). Manufactured axi-cel was within specification for 100% of the CNS cohort. There was a higher rate of bridging therapy use in the CNS cohort 82% (1 steroids only, 2 radiation therapy, 12 systemic therapy) vs 52% in non-CNS cohort; p=0.022. Time from leukapheresis to CAR T infusion was 3.5 days longer in the CNS cohort as opposed to the non-CNS cohort: median time of 29.5 (range 20-76) vs. 26 days (range 5-67), (p=0.029), respectively. The CAR T infusion rate was 88% for the CNS cohort (15/17) compared to 93% (262/283) in the non-CNS cohort. Among the 15 infused pts in the CNS cohort, 10 had resolution of CNS involvement, and 5 had persistent active CNS disease at time of CAR T infusion.
After axi-cel infusion, the incidence of CRS and ICANS, of any grade or grade 3 or higher, were comparable between the CNS and non-CNS cohorts. Tocilizumab and steroid use were comparable between the two groups (Panel B). No seizures or cerebral edema were noted in the CNS cohort.
With a median follow-up of 10.1 months from leukapheresis (range 7.6-12.6), the ITT best overall response rates (CR+PR) and ongoing responses at month 6 between CNS and non-CNS cohorts were 75% vs. 59%, and 41% vs. 31%, respectively (Panel B). In the 5 pts with active CNS disease at time of CAR T infusion, the response of CNS disease were 2 CR, 1 PR and 2 PD as best response. In the 10 pts with resolved CNS disease at time of CAR T infusion, 2 PD were seen and both occurred systemically. EFS from leukapheresis was not statistically significantly different between CNS and non-CNS cohorts (6 months EFS: CNS cohort, 36%; non-CNS cohort 57%. HR=1.58, 95% CI: 0.83-3.01, p=0.16, Panel C). Six month EFS from the date of infusion for the CNS cohort was 49.9% (Panel D).
Conclusions: Pts attempting CAR T therapy with secondary CNS disease in the real world setting had similar rates of CAR T infusion, toxicity, and outcomes when compared to patients without CNS disease. Small sample size and limited follow-up caution the strength of conclusions for application to clinical practice, but these results support further investigation of CAR T in pts with history of or active secondary CNS lymphoma.
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Bennani:Seattle Genetics: Other: Advisory board; Adicet Bio: Other: Advisory board; Purdue Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Purdue Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Kite Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Adicet Bio: Other: Advisory board; Adicet Bio: Other: Advisory board; Kite Pharma: Other: Advisory board. Maurer:Celgene: Research Funding; Nanostring: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees. Nastoupil:Bayer: Honoraria; Spectrum: Honoraria; TG Therapeutics: Honoraria, Research Funding; Novartis: Honoraria; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Genentech, Inc.: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Jain:Kite/Gilead: Consultancy. Chavez:Novartis: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees. Cashen:Seattle Genetics: Other: Speaker's Bureau; Novartis: Other: Speaker's Bureau; Celgene: Other: Speaker's Bureau. Reagan:Kite, A Gilead Company: Consultancy; Curis: Consultancy; Seattle Genetics: Research Funding. Oluwole:Pfizer: Consultancy; Spectrum: Consultancy; Gilead Sciences: Consultancy; Bayer: Consultancy. McGuirk:Novartis: Research Funding; Fresenius Biotech: Research Funding; Astellas: Research Funding; Bellicum Pharmaceuticals: Research Funding; Kite Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gamida Cell: Research Funding; Pluristem Ltd: Research Funding; ArticulateScience LLC: Other: Assistance with manuscript preparation; Juno Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Deol:Novartis: Other: Advisory board; Kite: Other: Advisory board; Agios: Other: Advisory board. Sehgal:Juno/Celgene: Research Funding; Merck: Research Funding; Kite/Gilead: Research Funding. Goy:COTA: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: leadership role for profit healthcare company; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astrazenca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; University of Nebraska: Research Funding; Hakensackumc: Research Funding; Takeda: Other: Grants outside of the submitted work; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work; Pharmacyclics/Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work, Research Funding; Genentech: Other: Grants outside of the submitted work, Research Funding; Hackensack University Medical Center, RCCA: Employment; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work, Research Funding. Hill:Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG therapeutics: Research Funding; AstraZeneca: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Celegene: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Research Funding; Takeda: Research Funding; Amgen: Research Funding. Vu:Celgene: Other: Stock. Andreadis:Genentech: Equity Ownership, Other: Spouse is Employee; Novartis: Honoraria, Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Gilead: Consultancy; Jazz Pharmaceuticals: Consultancy; Bayer: Consultancy. Munoz:Incyte: Research Funding; Portola: Research Funding; Celgene: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Speakers Bureau; AstraZeneca: Speakers Bureau; Pharmacyclics LLC an AbbVie Company: Consultancy, Research Funding, Speakers Bureau; Kite Pharma: Consultancy, Research Funding, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Fosunkite: Speakers Bureau; Kyowa: Consultancy, Honoraria, Speakers Bureau. Vose:Acerta Pharma: Honoraria, Other: Grants, Research Funding; Bristol-Meyers Squibb Company: Research Funding; Celgene Corporation: Research Funding; Incyte Corporation: Research Funding; Kite Pharma: Honoraria, Other: Grants, Research Funding; Novartis: Research Funding; Seattle Genetics: Research Funding; AbbVie: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Legend Phar
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