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\begin{document}

\title{T Lymphoblastic Lymphoma with BCR-ABL Negative Chronic Myeloid Leukaemia
\ldots{}a Novel Association}



\author[1]{Mahwish Faizan}%
\author[1]{Saadia Anwar}%
\author[1]{Rahat Ul Ain}%
\author[2]{Huma  Zafar}%
\author[2]{Nazish Saqlain}%
\author[1]{Zunaira Rathore}%
\affil[1]{The Children's Hospital and the Institute of Child Health}%
\affil[2]{The Children Hospital \& Institute of Child Health}%


\vspace{-1em}



  
  \date{May 18, 2024}


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\selectlanguage{english}
\begin{abstract}
Lymphoblastic Lymphoma and Chronic Myeloid leukemia are two distinct
neoplasms with different pathogenesis and clinical presentation. We
hereby share a challenging case of a child presenting with fever,
leucocytosis, generalized lymphadenopathy and massive splenomegaly. He
was diagnosed as having novel association of concurrent T-Lymphoblastic
Lymphoma diagnosed on cervical lymph node biopsy with BCR-ABL Negative
Chronic Myeloid leukemia on bone marrow aspirate. Study of more such
cases is needed for optimal patient management.%
\end{abstract}%



\sloppy


\textbf{INTRODUCTION;}

Acute lymphoblastic leukemia /lymphoma (LBL) is a clonal hematopoietic
stem cell disorder of B or T cell origin.~LBL comprise approximately
30\% of childhood Non Hodgkin Lymphomas. Chronic myeloid leukaemia (CML)
constitutes 2--3\% of leukaemia in children. Atypical CML (BCR-ABL
negative) is a challenging myeloid malignancy with features of both
myeloproliferative and myelodysplastic syndromes. The diagnosis of both
myeloid and lymphoid neoplasms in a single patient, whether simultaneous
or sequential, is extremely rare, with an overall incidence of less than
1\% \textsuperscript{1}. Our reported case has concurrent T
Lymphoblastic Lymphoma and BCR-ABL Negative CML, which has never been
reported in the literature before.

\textbf{CASE REPORT;}

A 9 years old child presented to oncology clinic in September 2020 with
six months history of fever, fatigue and gradually increasing bilateral
neck swellings. There was no complain of cough, respiratory distress,
bone pains, peteciae or bruises. He was pale looking, active and alert
child having weight of 22 Kg. BCG scar was present. He had generalized
lymphadenopathy, largest were bilateral cervical lymph nodes 5 by 5 cm,
discrete, firm, non-tender with normal overlying skin. He had
hepatomegaly of 4 cm below right costal margin with splenomegaly of 12
cm below left costal margin. Rest of systemic examination was normal.
His Haemoglobin was 6.9 gm/dl, WBC 168.4 8*10\textsuperscript{3}/l,
neutrophils 36\%, lymphocytes 02\%, eosinophils 07\%, monocytes 02\%,
promyelocytes 02\%, myelocytes 26\%, metamyelocytes 16\%, basophils
07\%, blasts 02\%, MCV 80.1 fl, MCH 26.4 pg, Peripheral blood film shows
macrocytosis, anisocytosis, and poikilocytosis. Nucleated red blood
cells 03/100 WBC. No hemoparasites were identified. Platelets 72,000/l.
serum uric acid 7.2 md/dl, potassium 4 mmol/l, LDH 780.
Echocardiography, hepatitis B \& C screening, calcium, phosphate, liver
and renal function tests were normal. CT neck, chest, abdomen showed
bilateral cervical, axillary, supraclavicular, mediastinal and abdominal
lymphadenopathy, hepatosplenomegaly and splenic parenchymal defects
suggesting lymphoproliferative disorder. Flow cytometry on bone marrow
aspirate was inconclusive showing less than 5 \% blasts. Bone Marrow
aspirate morphology showed Hyper cellular fragments showing active
trilineage haematopoiesis. Blasts constitute 5\%of nucleated marrow
cells. Plasma cells constitute 3\% of nucleated marrow cells. No
hempparasites identified. Blasts cell constitute 08\% of nucleated
marrow cells. BM differential was myelocytes 40\%, metamyelocytes 02\%,
erythroids 05\%, neutrophils 45\%, and blasts cells 08\%. Bone Marrow
trephine biopsy was adequate length with normal bony trabeculae, reduced
fat spaces, and 95\% cellularity (Fig1). Erythropieiss supressed with
hyperplastic myelopoiesis, megakaryopoiesis seen. Peripheral film and
bone marrow findings were suggestive of Chronic Myeloproliferative
Disorder most likely Chronic Myelogenous Leukaemia in chronic Phase.
Excisional biopsy of cervical lymph node was CD 3 positive, CD 20
negative, Tdt positive, cyclin D-1 negative, and KI 67 High
(\textgreater{}80\%) consistent with T cell Lymphoblastic Lymphoma
/Leukaemia (Fig11). BCR-ABL Translocation was not detected on RT-PCR.
Differential diagnosis considered included CML with Lymphoma,
lymphadenopathy as an extrahematopietic manifestation of CML or myeloid
sarcoma. Considering the rarity of association of T lymphoblastic
Lymphoma/leukaemia with BCR ABL negative CML in paediatric age group,
both the cervical lymph node biopsy and Bone marrow aspiration biopsy
were sent for external review, after discussion in tumour board meeting.
Both reports corresponded to and confirmed the primary diagnosis of T
lymphoblastic Lymphoma with BCR ABL negative CML which in unheard of, in
paediatric population. The family was appropriately counselled. The
child was started T lysis and pneumocystis jerovecci prophylaxis,
hyperhydraion, and antibiotics. Literature was searched to make optimal
treatment plan for this child. There was paucity of data to make exact
recommendation of treatment. Family was counselled about bone Marrow
Transplant when his lymphoblastic is in remission, to which they did not
consent. The child was started on UKALL 2011 induction.

\textbf{DISCUSSION;}

Lymphoma is the third most common childhood malignancy accounting for
10-12\% of childhood cancers. NHL account for 7\% of cancers in children
\textless{}20 yrs of age\textsuperscript{2} . T-LBL is the most common
paediatric T cell Lymphoma. They develop in lymphoid tissues such as
lymph nodes and spleen or outside of lymphoid tissues like
gastrointestinal tract, liver, nasal cavity, skin etc. CML is rare in
children \& constitutes 2\% of all leukemias in children younger than 15
years and 9\% of all leukemias in adolescents between 15 and 19
years\textsuperscript{3}About 90-95 percent of children with CML have a
genetic alteration called the Philadelphia chromosome.

Atypical chronic myeloid leukemia,~\emph{BCR-ABL1} ~negative (aCML) is a
rare myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) in
children.~Currently, the diagnosis of aCML is reached primarily on
morphology-based criteria. The main feature characterizing aCML is the
presence of neutrophilic leucocytosis and marked dysgranulopoiesis.
Moreover, to fulfil the diagnostic criteria, WBC should be [?] 13 \selectlanguage{ngerman}×
10\textsuperscript{9}/L with \selectlanguage{english}[?] 10\% of immature granulocytes, and \selectlanguage{english}[?] 20\%
blasts in the blood and the BM \textsuperscript{4,5}\textsubscript{.} To
rule out other myeloproliferative disorders,~\emph{BCR-ABL1}
~rearrangement should be excluded in all cases\textsuperscript{6}.

There has been case report of secondary malignancies in
CML\textsuperscript{7} . Fu X et al\textsuperscript{9} reported
simultaneous diagnosis of T-LBL and BCR-ABL positive CML in two adult
patients reported which were treated with imatinib and HYPER-CVAD.
Chemotherapy. Simultaneous AML and lymphoma has been reported in
literature and is more frequent than simultaneous CML and
lymphoma\textsuperscript{9}. Melikian AL etal reported 20 adult patients
with synchronous and metachronous tumors\textsuperscript{10}.

Our index patient fulfilled the criteria of both T-NHL based on
immunohistochemistry and typical morphology on lymph node biopsy and
BCR-ABL negative CML on Bone marrow. This association, till to date, has
not been previously described in literature both in adults and children.
Due to rarity of this co existence, little is known about pathogenesis
and optimal treatment plan.

T-NHL is an aggressive malignancy but with the development of
intensified T-ALL--focused protocols has resulted in significant
improvements in outcome in children \textsuperscript{11.}~No standard of
care is currently available for aCML management. Drugs called~tyrosine
kinase inhibitors~(TKIs) are the first line of treatment for BCR ABL
positive CML. However, the only curative treatment for atypical CML
remains HSCT \textsuperscript{12,} an option available for the younger
patients only. Participation on clinical trials should be considered in
all cases. Different treatment options like hypomethylating agents
(azacytidine or decitabine)\textsuperscript{13}, Hydroxy urea.
Interferon alpha, AML like therapy or targeted therapies (JAK inhibitor
ruxolitinib, the SRC kinase inhibitor dasatinib, and the MEK inhibitor
trametinib) have been used with variable results in patients not
suitable for BMT \textsuperscript{14,15}. The prognosis of the
concurrent bi-lineage malignancies is generally poorly understood and
chemotherapy is necessary.~More cases are required to optimize
management for such children.

\textbf{CONFLICT OF INTEREST;}

No conflict of interest

\textbf{ACKNOWLEDGEMENTS;}

Haematology Lab team, Agha Khan university Hospital, Karachi, Pakistan
for secondary review \& Paediatric Oncology Eastern and Mediterranean
Group (POEM) for MDT discussion.

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\section*{}

{\label{section}}

Crisa Elena, Nicolosi M, Ferri V et al. Atypical Chronic Myeloid
Leukemia: Where Are We Now? Int. J. Mol. Sci.~2020,~21(18),
6862;~https://doi.org/10.3390/ijms21186862.

\section*{}

{\label{section-1}}

Legends;

Fig 1; Bone Marrow Trephine Biopsy

Fig 11; Cervical Lymph Node Biopsy (Terminal deoxynucleotidyl
transferase/

Tdt positive)

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\verb`Fig 1 .docx`  available at \url{https://authorea.com/users/337265/articles/562109-t-lymphoblastic-lymphoma-with-bcr-abl-negative-chronic-myeloid-leukaemia-a-novel-association}

\textbf{Hosted file}

\verb`Fig 11.docx`  available at \url{https://authorea.com/users/337265/articles/562109-t-lymphoblastic-lymphoma-with-bcr-abl-negative-chronic-myeloid-leukaemia-a-novel-association}

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