Primary isolated central nervous system acute lymphoblastic leukemia with BCR-ABL1rearrangement:A case report

lNTRODUCTlON

Acute leukemia(AL)is a malignancy hematologic disease of bone marrow(BM)-derived immature cells,which most often involves the BM and peripheral blood but may also manifest in extramedullary tissue.Acute lymphocytic leukemia(ALL)patients appear to have a higher incidence of central nervous system(CNS)disease than acute myelogenous leukemia.CNS leukemia can be present at the initial diagnosis concurrent with bone marrow involvement,but it also can develop at any time during the natural course of AL,even after years of complete remission,as isolated CNS relapse[1].In a few cases,leukemia cells are isolated to the CNS primarily without involvement of bone marrow.However,these cases are all non-lymphoid leukemia[2-4].We here report a rare case of newly diagnosed

positive ALL primarily located in the superficial arachnoid and the subarachnoid space,clinically manifesting as leukemic meningitis,without peripheral blood or bone marrow involvement.

The next day he went out to hunt, and when he came home the first thing he did was to go up to the doll and brush off some of the ashes from the fire which had fallen on its face

CASE PRESENTATlON

Chief complaints

A 30-year-old Chinese woman presented with 2 mo history of unsteadiness while walking starting in May 2020.

History of present illness

A mo later,she presented with progressive difficulty in walking and both lower limbs dragging.

History of past illness

She denied a history of fever,wasting and night sweats.

Personal and family history

Written informed consent was obtained from the patient for publication of this case report.

Physical examination

On physical examination,no lymphadenopathy or organomegaly was detected.The myodynamia of left distant and proximate limb were grade 5- and grade 3+ respectively.The myodynamia of right distant and proximate limb were grade 5- and grade 4- respectively.Meningeal stimulation sign was negative.Cranial nerve examination and sensory examination was within normal limits.

Laboratory examinations

Recent studies have shown that anti-CD19 chimeric antigen receptor(CAR)T cell effectively and safely eliminate leukemia cells in the CNS[14,15].Some patients who received no further therapy for CNS leukemia after CAR-T cells infusion experienced sustained remission for more than 5 mo.Cellular therapies may be able to cross blood-brain barrier in the brain.But systematic studies with larger amount of patients are needed to evaluate the superiority of CAR-T cells in CNS leukemia.

Flow cytometry of lumbar puncture indicated an aberrant lymphoblast population(92.8%);expression of cells of differentiation(CD)19,CD10,CD34,human leukocyte antigen D related,CD13,and cCD79a;and absence of CD33,CD117,CD20,CD7,CD15,and cytoplasmic myeloperoxidase(Figure 2).Immunophenotype was consistent with pre-B cell-ALL.Polymerase chain reaction(PCR)screening covered 56 transcripts of myeloid fusion proteins and 15 transcripts of lymphoblastic fusion proteins,and showed the presence of

chimeric oncogene,encoding proteins of 190 kDa(p190)in CSF.This was quantified by real-time reverse transcriptase-PCR assay and found to be 24.061%(Table 1).Fluorescence in situ hybridization from the CSF revealed that 89.5% of the 200 cells screened had

fusion signals(Figure 3).Next-generation sequencing for

kinase domain mutation of CSF malignant cells did not show any mutations.

Bone marrow biopsies were performed several times,and were normocellular by flow cytometry and cytological analysis.No genetic mutations were found in BM by next-generation sequencing(NGS).PCR screening of the same transcripts with CNS was negative and indicated absence of

(p190).

After the mastectomies, I knew that one way to get myself going would be to start exercising again, so I headed for the local pool. In the communal9 shower, I found myself noticing other women s breasts for the first time in my life. Size-D breasts and size-A breasts, sagging10 breasts and perky breasts. Suddenly and for the first time, after all these years of missing a leg, I felt acutely self-conscious. I couldn t bring myself to undress.

Imaging examinations

The authors declared that they have no conflicts of interest regarding this work.

FlNAL DlAGNOSlS

Primary isolated central nervous system acute lymphoblastic leukemia with

rearrangement.

TREATMENT

The patient initially received chemotherapy on July 23,2020.Treatment consisted of methotrexate(3.5 g/m

)on day 1 plus cytarabine(2 g/m

)on day 2 and was combined with triple intrathecal chemotherapy including methotrexate 10 mg,cytarabine 50 mg and dexamethasone 5mg twice a week.After the treatments for 3 wk,she was free from symptoms.CSF cytology,flow cytometry,and

(p190)transcripts remained positive.She then underwent three cycles of methotrexate(3.5 g/m

)in combination with cytarabine(2 g/m

)twice daily on days 2 and 3,with repeating treatment every 3 wk and seven courses of intrathecal chemotherapy.CSF cytology became negative,but the disease remained detectable by flow cytometry in September 30,2020.Due to financial reasons,the patient discontinued treatment.

OUTCOME AND FOLLOW-UP

She returned 4 mo later reporting the same symptoms with positive CSF cytology.Peripheral blood and bone marrow continued to be negative by flow cytometry.The patient received dasatinib(140 mg/d)in combination with steroids and intrathecal agents,but dasatinib was discontinued after 4 wk due to hematologic toxicity.After myelosuppression recovery,CSF cytology remained positive.The patient rejected further systemic drugs and only accepted intrathecal triple therapy intermittently.The patient is currently alive,with positive CSF cytology in September 2021.

DlSCUSSlON

fusion is associated with a higher incidence of CNS leukemia than other B cell precursor-ALL[5].Here,we report a case of

positive for ALL that was primarily isolated to CNS with no involvement in blood or bone marrow.Given the rarity of this condition,no standard diagnostic assessment or treatment is currently available.The most valuable diagnostic procedure was the detection of aberrant cells in the CSF.PET-CT and MRI can exclude brain parenchyma and spinal cord occupancy.Laboratory techniques including molecular biology,molecular genetics,and flow cytometry in combination with cytology improved diagnostic accuracy in the ALL with unique presentation[6-8].In the present case,identification of abnormal phenotype of blast cells,and

rearrangement in the CSF alone established the diagnosis of primary CNS-isolated ALL.

Grampy held my hand tightly. Together we looked up the street and down, and back up again. He stepped off the curb and told me it was safe to cross. He let go of my hand and I ran. I ran faster than I had ever run before. The street seemed wide. I wondered if I would make it to the other side. Reaching the other side, I turned to find Grampy. There he was, standing14 exactly where I had left him, smiling proudly. I waved.

CSF examination is the most useful laboratory test in the diagnosis of the rare primary CNS-isolated ALL.Flow cytometry in combination with PCR/NGS analyses improved diagnostic accuracy and facilitated subsequent analysis of minimal residual disease.Current CNS leukemia treatment strategies are not specific and associated with long-term toxicity.CAR-T cell therapy is a new and promising approach that may improve the efficacy of the existing therapies and eliminate CNS leukemia cells.

Because this is a CNS-restricted disease,treatment protocols were based on the diagnosis of primary CNS lymphoma.The patient showed a clinical response to systemic and intrathecal chemotherapy.High-dose chemotherapy with stem-cell rescue was strongly recommended,but she declined.Unfortunately,the benefits of the treatments were short-lived and she experienced recurrence.

How it could be that I moved her just one day, some neighbour ordered about the child to borrow things, wasn t that to bully1 the newcomer? Today, I lent you a candle, maybe tomorrow you would come here to brorrow onions, gingers2（） and garlics, no, no! The hostess then replied, Ah, unfortunately, I just moved here, and don t prepare candles. With that, she got ready to close the door.

CSF blast cells did not show any

kinase domain mutation by sequencing.Imatinib does not penetrate the CNS well[9].Dasatinib has been reported to exhibit better penetration into the CSF than imatinib in in vitro studies[10].However,the use of a higher dasatinib dosage(140 mg/d)was unable offer a proper control of the patient’s CNS leukemia.Other case reports also presented that dasatinib failed to prevent CNS progression[11-13].Factors except for

kinase domain mutations might influence dasatinib efficacy in the CNS,such as dose intensity of dasatinib,lack of protein binding,and comedications known to decrease dasatinib plasma concentrations,but data are limited in this regard to come to a conclusion.

The mechanisms fostering primary CNS leukemia are unknown.CNS involvement is a difficult problem in the treatment of ALL.In order to develop novel treatment programmers,it is essential to investigate the molecular mechanisms of CNS leukemia.

Complete blood counts showed white blood cells 4.08 × 10

/L(normal: 4-10 × 10

/L),hemoglobin 134 g/L(normal: 110-160 g/L),and platelets 280 × 10

/L(normal: 100-300 × 10

/L).Peripheral blood smears were negative.Lumbar puncture demonstrated increased opening pressure(220 mm H

O)and was hypercellular with numerous large malignant cells in cerebrospinal fluid(CSF)(Figure 1).As central nervous system leukemia was suspected,the patient referred to our hematology department for further evaluation.

CONCLUSlON

Communication with Dad was, at its best, on the surface. We knew he loved us and he knew we loved him, but the words were seldom spoken aloud. And none of us ever mentioned our relationship with Gordon.

FOOTNOTES

Lu QY designed the research;Lu JY and Hong XL performed the research;Chen Y analyzed the data and wrote the manuscript;all authors have read and approve the final manuscript.

And it had a lot of people that didn t always see eye to eye（）, like a lot of other cities. And it had a rich man, like almost every other town. And this rich man was a pillar in the Baptist Church; and people didn t see eye to eye about him, either.

the Science and Technology Plan Guide Project of Fujian Province,No.2019D009.

The next that came into the world was the most beautiful little prince, and he was shown to the king and queen, who knew nothing about his brother the lindorm

She had no personal or family history of malignancy.

There were no obvious abnormalities on brain and spine magnetic resonance imaging(MRI).Positron emission tomography-computed tomography(PET-CT)scans demonstrated no hypermetabolic involvement in other areas.There was no evidence of occuping diseases.

The authors have read the CARE Checklist(2016),and the manuscript was prepared and revised according to the CARE Checklist(2016).

This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers.It is distributed in accordance with the Creative Commons Attribution NonCommercial(CC BYNC 4.0)license,which permits others to distribute,remix,adapt,build upon this work non-commercially,and license their derivative works on different terms,provided the original work is properly cited and the use is noncommercial.See: https://creativecommons.org/Licenses/by-nc/4.0/

China

Yan Chen 0000-0002-7804-9897;Quan-Yi Lu 0000-0001-5133-720X;Jing-Yuan Lu 0000-0002-1386-8891;Xiu-Li Hong 0000-0002-5104-2548.

Guo XR

A

28. Drunken hussar: A hussar is a European solider, usually a cavalry72 officer. Von Franz points out that the hussar, symbolizes a brutal73 outburst of emotion. The wild ungovernable animus smashes everything, showing clearly that such an exhibition of her unconscious nature does not work (175). This is also another aspect of Wotan (von Franz 175). According to von Franz, the horse the hussar rides is connected to the animus and respects instinctive74 animal nature (176).Return to place in story.

Guo XR

1 Deak D,Gorcea-Andronic N,Sas V,Teodorescu P,Constantinescu C,Iluta S,Pasca S,Hotea I,Turcas C,Moisoiu V,Zimta AA,Galdean S,Steinheber J,Rus I,Rauch S,Richlitzki C,Munteanu R,Jurj A,Petrushev B,Selicean C,Marian M,Soritau O,Andries A,Roman A,Dima D,Tanase A,Sigurjonsson O,Tomuleasa C.A narrative review of central nervous system involvement in acute leukemias.

2021;9: 68[PMID: 33553361 DOI: 10.21037/atm-20-3140]

2 Liu H,Guinipero TL,Schieffer KM,Carter C,Colace S,Leonard JR,Orr BA,Kahwash SB,Brennan PJ,Fitch JR,Kelly B,Magrini VJ,White P,Wilson RK,Mardis ER,Cottrell CE,Boué DR.

primary central nervous system pure erythroid leukemia/sarcoma with t(1;16)(p31;q24)

translocation.

2020;105: e194-e197[PMID: 31949013 DOI: 10.3324/haematol.2019.231928]

3 Celebisoy N,Bayam FE,Cağirgan S,Hekimgil M.Primary central nervous system leukemia presenting with an isolated oculomotor palsy.

2008;15: 1144-1145[PMID: 18710807 DOI: 10.1016/j.jocn.2007.09.021]

4 Park C,Suh D,Ramey A,Heston C,Abromowitch M.Isolated central nervous system primary acute monoblastic leukemia presenting as papilledema.

2016;63: 2256-2257[PMID: 27569601 DOI:10.1002/pbc.26152]

5 Sanchez R,Ayala R,Alonso RA,Martínez MP,Ribera J,García O,Sanchez-Pina J,Mercadal S,Montesinos P,Martino R,Barba P,González-Campos J,Barrios M,Lavilla E,Gil C,Bernal T,Escoda L,Abella E,Amigo ML,Moreno MJ,Bravo P,Guàrdia R,Hernández-Rivas JM,García-Guiñón A,Piernas S,Ribera JM,Martínez-López J.Clinical characteristics of patients with central nervous system relapse in BCR-ABL1-positive acute lymphoblastic leukemia: the importance of characterizing ABL1 mutations in cerebrospinal fluid.

2017;96: 1069-1075[PMID: 28451802 DOI:10.1007/s00277-017-3002-1]

6 Bromberg JE,Breems DA,Kraan J,Bikker G,van der Holt B,Smitt PS,van den Bent MJ,van't Veer M,Gratama JW.CSF flow cytometry greatly improves diagnostic accuracy in CNS hematologic malignancies.

2007;68: 1674-1679[PMID: 17502548 DOI: 10.1212/01.wnl.0000261909.28915.83]

7 Gaipa G,Cazzaniga G,Valsecchi MG,Panzer-Grümayer R,Buldini B,Silvestri D,Karawajew L,Maglia O,Ratei R,Benetello A,Sala S,Schumich A,Schrauder A,Villa T,Veltroni M,Ludwig WD,Conter V,Schrappe M,Biondi A,Dworzak MN,Basso G.Time point-dependent concordance of flow cytometry and real-time quantitative polymerase chain reaction for minimal residual disease detection in childhood acute lymphoblastic leukemia.

2012;97: 1582-1593[PMID: 22581001 DOI: 10.3324/haematol.2011.060426]

8 Wood B,Wu D,Crossley B,Dai Y,Williamson D,Gawad C,Borowitz MJ,Devidas M,Maloney KW,Larsen E,Winick N,Raetz E,Carroll WL,Hunger SP,Loh ML,Robins H,Kirsch I.Measurable residual disease detection by highthroughput sequencing improves risk stratification for pediatric B-ALL.

2018;131: 1350-1359[PMID: 29284596 DOI: 10.1182/blood-2017-09-806521]

9 Takayama N,Sato N,O'Brien SG,Ikeda Y,Okamoto S.Imatinib mesylate has limited activity against the central nervous system involvement of Philadelphia chromosome-positive acute lymphoblastic leukaemia due to poor penetration into cerebrospinal fluid.

2002;119: 106-108[PMID: 12358909 DOI: 10.1046/j.1365-2141.2002.03881.x]

10 Porkka K,Koskenvesa P,Lundán T,Rimpiläinen J,Mustjoki S,Smykla R,Wild R,Luo R,Arnan M,Brethon B,Eccersley L,Hjorth-Hansen H,Höglund M,Klamova H,Knutsen H,Parikh S,Raffoux E,Gruber F,Brito-Babapulle F,Dombret H,Duarte RF,Elonen E,Paquette R,Zwaan CM,Lee FY.Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome-positive leukemia.

2008;112: 1005-1012[PMID: 18477770 DOI: 10.1182/blood-2008-02-140665]

11 Papageorgiou SG,Pappa V,Economopoulou C,Tsirigotis P,Konsioti F,Ionnidou ED,Chondropoulos S,Vasilatou D,Papageorgiou E,Economopoulos T,Dervenoulas J.Dasatinib induces long-term remission in imatinib-resistant Philadelphia chromosome-positive acute megakaryoblastic leukemia but fails to prevent development of central nervous system progression.

2010;34: e254-e256[PMID: 20392492 DOI: 10.1016/j.leukres.2010.03.032]

12 Frigeri F,Arcamone M,Luciano L,Di Francia R,Pane F,Pinto A.Systemic dasatinib fails to prevent development of central nervous system progression in a patient with BCR-ABL unmutated Philadelphia chromosome-positive leukemia.

2009;113: 5028-5029[PMID: 19443672 DOI: 10.1182/blood-2008-11-191080]

13 Kiran PK,Badarke GV,Suresh CN,Srinivas BJ,Naik R.Isolated central nervous system blast crisis in a case of chronic myeloid leukemia on dasatinib.

2018;7: 170[PMID: 30112332 DOI: 10.4103/sajc.sajc_63_18]

14 He X,Xiao X,Li Q,Jiang Y,Cao Y,Sun R,Jin X,Yuan T,Meng J,Ma L,Lu W,Lyu C,Liu K,Zhao M.Anti-CD19 CAR-T as a feasible and safe treatment against central nervous system leukemia after intrathecal chemotherapy in adults with relapsed or refractory B-ALL.

2019;33: 2102-2104[PMID: 30846865 DOI: 10.1038/s41375-019-0437-5]

15 Rheingold SR,Chen LN,Maude SL,Aplenc R,Barker C,Barrett DM,Callahan C,Cebry K,Kulikovskaya I,Lacey SF.Efficient trafficking of chimeri antigen receptor(CAR)-modified T cells to CSF and induction of durable CNS remissions in children with CNS/combined relapsed/refractory ALL.

2015;58: 434-442[DOI: 10.1080/08977190802227828]