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\begin{document}

\title{Patient with Down syndrome and relapsed acute lymphoblastic leukemia
with sustained remission despite only partial British R3 chemotherapy}



\author[1]{Zhongbo Hu}%
\author[1]{Kristen VanHeyst}%
\author[1]{Jignesh Dalal}%
\author[1]{Lisa Hackney}%
\affil[1]{UH Rainbow Babies and Children's Hospital}%


\vspace{-1em}



  
  \date{June 16, 2024}


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\begin{abstract}
DS-ALL patients have a higher rate of relapse and treatment-related
mortality. We describe a DS-ALL patient with late bone marrow relapse
who was treated per British ALL R3 reinduction chemotherapy. The patient
remained in remission for approximately two years after therapy was
discontinued due to severe systemic infections.%
\end{abstract}%



\sloppy


\textbf{Key clinical message}

DS-ALL has a higher rate of relapse and treatment-related mortality.

Relapsed ALL with positive MRD has a poor prognosis.

Transient long-term remission after ALL relapse due to partial
chemotherapy combined severe infection is rare.

\textbf{INTRODUCTION}

The current treatment regimens for acute lymphoblastic leukemia (ALL)
have successfully attained cure-rates of approximately 90-95\% in
children, but still with poor overall long-term survival in adults of
about 40\% \textsuperscript{1-3}. It still remains a significant
challenge to improve the survival of patients with relapsed ALL.
Patients with relapsed ALL have a suboptimal
prognosis\textsuperscript{1, 4}. Down syndrome patients (DS) with
relapsed ALL have even worse outcomes. DS itself was proven to be an
independent prognostic factor of outcome after ALL
relapse.\textsuperscript{5} ALL patients with DS have a higher rate of
relapse and treatment related mortality, with an 8-year cumulative
incidence of relapse of 26\% comparing with 15\% in non-DS patients and
a 2-year treatment-related mortality of 7\% with 2\% in the
latter.\textsuperscript{6} There are several case reports of patients
with leukemia who attained spontaneous remission after severe infection
\textsuperscript{7-9}. There are no reports of a patient with relapsed
leukemia with sustained remission following cessation of therapy
secondary to severe infections, except an older patient with relapsed
FLT3 internal tandem duplication mutant acute myeloid leukemia whose
disease underwent spontaneous remission for 35 days without
precipitating cause \textsuperscript{10}.

We describe a case of a 37 year-old man with Down syndrome and ALL
(DS-ALL) who had a late bone marrow relapse and sustained remission for
2 years after only receiving two cycles of ALL R3 salvage chemotherapy
due to severe systemic infections.

\textbf{CASE PRESENTATION}

A 30 year-old male with Down syndrome presented with fever, cough, and
shortness of breath in November 2013. He was managed in our pediatric
unit because of current favorable outcomes for Adolescents and Young
Adults (AYA) with ALL treating with pediatric COG
protocols.\textsuperscript{11} His complete blood count (CBC) showed
pancytopenia with a white blood cell (WBC) count of 1.4 x 10\^{}9/L,
hemoglobin of 8.3 g/dL, and platelet count of 32 x 10\^{}9/L with
occasional circulating blasts. Bone marrow aspirate and biopsy confirmed
the diagnosis of acute lymphoblastic leukemia with 73\% blasts which
co-expressed CD34, CD19, CD10 and TdT with aberrant expression of dim
CD33 by flow cytometry, which was consistent with B-precursor ALL.
Cytogenetic analysis was not successful but FISH from a bone marrow
sample obtained on day 17 during Induction chemotherapy as per the
Children's Oncology Group (COG) study AALL1131 showed nuc
ish(ETV6x2,RUNX1x3){[}250{]} which was a normal signal pattern for
constitutional trisomy 21 with two ETV6 signals and three RUNX1 signals.
Diagnostic cerebrospinal fluid was negative for blasts.

The patient was treated per COG high risk protocol AALL1131, Down
syndrome arm due to NCI risk factor for age above 10 years old. He had a
rapid early response with a M1 marrow at Day 17 and he achieved complete
remission after Induction with negative minimal residual disease (MRD).
He had a complicated treatment course including a few episodes of
sepsis, one of which included multi-organ failure for which he was in
the Medical ICU, and PICC line associated DVT, Following the end of his
treatment, his platelet count never normalized and ranged between
90x10\^{}9/L and 112x10\^{}9/L. At his lowest level of thrombocytopenia
to 48x10\^{}9/L in September 2017, which was four years after the
initial diagnosis, a repeat bone marrow aspirate and biopsy was obtained
and showed a 90\% cellular bone marrow with 82\% blasts, consistent with
late bone marrow relapse. FISH showed CRLF2 translocation positive in
63.5\% of cells and was also positive for deletion of CDKN2A on
chromosome 9p beside his constitutional trisomy of chromosome 21. CNS
was negative. This relapse was treated with Reinduction chemotherapy per
ALL R3 protocol (Dexamethasone 20mg/m2/day day 1-5 \& 15-19,
Mitoxantrone 10mg/m2/dose day 1-2, Vincristine 1.5mg/m2/dose from day 3,
then weekly; PEG-asparaginase 2500U/M2 day 3 and 18; Intrathecal
Methotrexate day 1 and 8). Post-reinduction day 29 MRD was 0.2\% (Table
1).

He continued to receive Consolidation chemotherapy per ALL R3 protocol
(Intrathecal Methotrexate day 1, Dexamethasone 6mg/m2/day day 1-5,
methotrexate 1000mg/m2/dose day 8 with Leucovorin rescue, Vincristine
1.5ng/m2/dose day 3, PEG-asparaginase 2500U/m2/dose day 9,
Cyclophosphamide 440mg/m2/dose day 15-19, Etoposide 100mg/m2/dose day
15-19), after which his bone marrow had negative MRD. While hospitalized
for Intensification chemotherapy, he developed sepsis, necrotizing
pneumonia, and severe bilateral pleural effusions. BAL revealed Candida
albicans. CT imaging also revealed near complete splenic infarct, right
renal perfusion deficits with signs of liquefaction and a segmental area
of abnormal small bowel wall enhancement and concern for focal small
bowel wall defect. He also developed delirium related to his severe
illness and prolonged hospitalization. Due to severe illness, his
chemotherapy was held during a three month period. A bone marrow after
three months continued to demonstrate negative MRD. Once he became more
clinically stable, chemotherapy was attempted with intermediate dosed
Methotrexate but this hospital course was complicated by infection
necessitating removal of his broviac, fluid overload, and a persistent
cavitary lung lesion. At this point, a decision was made by his family
and treatment team to stop chemotherapy. About 50 weeks after his
diagnosis of relapsed disease, a repeat bone marrow continued to
demonstrate negative MRD. He was followed closely as an outpatient.
Unfortunately, he presented with acute onset psychosis and
thrombocytopenia about 2 years after stopping his treatment and bone
marrow was consistent with relapsed disease. Family opted for no further
therapy and unfortunately the patient passed away 7 weeks later.

\textbf{DISCUSSION}

Despite current long-term remission with leukemia-free survival of ALL
reaching above 90\% in children \textsuperscript{1, 12}, relapsed ALL
and adult cases are still the most important obstacles for the cure of
ALL patients. The relapse rate is about 10-15\% of ALL in children, but
substantially higher (about 25-30\%) in high-risk
subgroups\textsuperscript{13, 14}. An estimated 40\% to 50\% of adult
patients with ALL experience relapse \textsuperscript{15}. DS patients
with ALL even have high relapse rate,\textsuperscript{6} partially due
to poor tolerance to anti-leukemia drugs.\textsuperscript{16} DS
patients more frequently develop severe infectious
complications.\textsuperscript{16}

Although high dose Mitoxantrone plus Cytarabine were effective in
achieving remission in refractory leukemia, the duration of the
remission was only about half a year \textsuperscript{17} and still
about 50\% of ALL patients do not respond to salvage therapy prior to
the ALL R3 protocol \textsuperscript{18}. The British ALL R3 protocol
utilizes Mitoxantrone to confer a significant response in
progression-free and overall survival in children with relapsed
ALL\textsuperscript{4}. Our patient, who had a bone marrow relapse about
20 months after the completion of his initial chemotherapy, was
considered to have late bone marrow relapse (defined as relapse
occurring 36 months after the first diagnosis or more than 6 months
after the end of front-line therapy). He was treated as per the ALL R3
protocol and had positive MRD of 0.2\% after Reinduction and negative
MRD after Consolidation. Per the ALL R3 protocol, patients with
B-precursor ALL with late bone marrow relapse and low MRD
(\textless{}0.01\%) at the end of induction had favorable outcomes with
chemotherapy without undergoing stem-cell transplantation. Patients with
higher MRD (\textgreater{}0.01\%) required allogeneic stem-cell
transplantation. But after long-term follow-up of the late bone marrow
relapse patients for 7 years, the second relapse rate was about 23\% in
the high MRD group even after stem cell transplant. We had discussed
this as a group for our patient and thought that his transplant related
mortality (TRM) would be too high given his toxicities with initial
chemotherapy and his Down syndrome status. We chose to continue
chemotherapy per ALL R3. In the low MRD group with chemotherapy, second
relapse rate was about 27\%\textsuperscript{19}. The progression-free
survival at 5 years was significantly lower in the high MRD group
comparing with that in the low MRD with 56\% versus
72\%\textsuperscript{19}. Our case is unique in that the patient was
still complicated with several systemic infection after only receiving
two phases of chemotherapy per the ALL R3 protocol for his first
relapse, but remained in remission for nearly two years.

Patients with Down syndrome are well-known to have 10- to 20-fold
increased risk of developing B-cell precursor
ALL.\textsuperscript{20}The Ponte di Legno study group showed that
DS-ALL patients had higher 8-year cumulative incidence of relapse than
non-DS patients (26\% vs 15\%) \textsuperscript{6}. AYA patients with
ALL have favorable outcomes when they are treated with pediatric
protocols.\textsuperscript{11}Treatment-related mortality, primarily
from infection, increased in all protocols in DS-ALL, which made both
the five-year event-free and overall survival inferior in patients with
DS-ALL \textsuperscript{21, 22}. Current COG protocols have made
modifications to limit toxicities. Our patient had multiple infections
during his initial chemotherapy per AALL1131. He also developed multiple
severe infections after two phases of chemotherapy per the ALL R3
protocol following disease relapse. Given the significant toxicity that
he experienced, a decision was made for cessation of therapy, which we
thought would benefit the patient better and was approved by patient's
parents. Over time, more options are becoming available for patients
with relapsed ALL that confer less toxicity. Currently,
antibody-targeted therapies, such as bispecific (CD3/CD19)
T-cell-engaging antibody Blinatumomab, Inotzumab, and CD19-directed
chimeric antigen receptor (CAR) T --cell therapies are major
breakthroughs in the management of relapsed
leukemia\textsuperscript{23}.

Spontaneous or transient remission of acute lymphoblastic leukemia
during severe infection has been described in a few cases and case
series reports with averaged ten weeks in duration \textsuperscript{7-9,
24}. The proposed mechanism was due to increased cortisol production
during stress or infection combined with an immune-mediated process
thereby generating anti-leukemic effects \textsuperscript{7, 8, 25}.
Cytokines, including tumor necrosis factor-alpha, interferon-alpha, and
interleukin-2, released during infection can directly inhibit the
residual blast proliferation or through increased activity of T
lymphocytes, macrophages, and natural killer cells leading to an
anti-leukemia effect \textsuperscript{26, 27}. Similar phenomena and
mechanisms have been discussed and reported in several cases and case
series in acute myeloid leukemia patients \textsuperscript{28, 29}. Our
patient's long-term remission may be attributed to a combination of the
two phases of chemotherapy per ALL R3 protocol with the systemic stress
related to his multiple severe infections.

\textbf{CONFLICTS OF INTEREST}

The authors declare no conflicts of interest.

\textbf{AUTHORS' CONTRIBUTIONS}

ZH: gathered the patient data, performed a literature review, and wrote
the manuscript. KAV, LH: reviewed, corrected patient data and revised
the manuscript. JD: was involved in overall supervision of the paper.
All authors: read and approved the final manuscript.

References

Uncategorized References

1. Hunger SP, Mullighan CG. Acute Lymphoblastic Leukemia in
Children.\emph{N Engl J Med} . Oct 15 2015;373(16):1541-52.
doi:10.1056/NEJMra1400972

2. Cooper SL, Brown PA. Treatment of pediatric acute lymphoblastic
leukemia. \emph{Pediatr Clin North Am} . Feb 2015;62(1):61-73.
doi:10.1016/j.pcl.2014.09.006

3. Pulte D, Jansen L, Gondos A, et al. Survival of adults with acute
lymphoblastic leukemia in Germany and the United States. \emph{PLoS One}
. 2014;9(1):e85554. doi:10.1371/journal.pone.0085554

4. Parker C, Waters R, Leighton C, et al. Effect of mitoxantrone on
outcome of children with first relapse of acute lymphoblastic leukaemia
(ALL R3): an open-label randomised trial. \emph{Lancet} . Dec 11
2010;376(9757):2009-17. doi:10.1016/S0140-6736(10)62002-8

5. Meyr F, Escherich G, Mann G, et al. Outcomes of treatment for
relapsed acute lymphoblastic leukaemia in children with Down
syndrome.\emph{Br J Haematol} . Jul 2013;162(1):98-106.
doi:10.1111/bjh.12348

6. Buitenkamp TD, Izraeli S, Zimmermann M, et al. Acute lymphoblastic
leukemia in children with Down syndrome: a retrospective analysis from
the Ponte di Legno study group. \emph{Blood} . Jan 2 2014;123(1):70-7.
doi:10.1182/blood-2013-06-509463

7. Iqbal A, Weinstein J, Angelova V, Dighe D, Giordano L. A Rare Case of
Spontaneous Remission of Terminal Deoxynucleotidyl Transferase Negative
B-acute Lymphoblastic Leukemia. \emph{J Pediatr Hematol Oncol} . Apr
2018;40(3):e176-e178. doi:10.1097/MPH.0000000000000906

8. Yoruk A, Erguven M, Celiker E, et al. Spontaneous remission of acute
lymphoblastic leukemia with mediastinal mass. \emph{Pediatr Hematol
Oncol} . Apr-May 2008;25(3):181-6. doi:10.1080/08880010801938132

9. Hores T, Wendelin K, Schaefer-Eckart K. Spontaneous remission of
acute lymphoblastic leukemia: A case report. \emph{Oncol Lett} . Jan
2018;15(1):115-120. doi:10.3892/ol.2017.7288

10. Vachhani P, Mendler JH, Evans A, et al. Spontaneous Remission in an
Older Patient with Relapsed FLT3 ITD Mutant AML. \emph{Case Rep Hematol}
. 2016;2016:1259759. doi:10.1155/2016/1259759

11. Stock W, Luger SM, Advani AS, et al. A pediatric regimen for older
adolescents and young adults with acute lymphoblastic leukemia: results
of CALGB 10403. \emph{Blood} . Apr 4 2019;133(14):1548-1559.
doi:10.1182/blood-2018-10-881961

12. Pal SK, Miller MJ, Agarwal N, et al. Clinical Cancer Advances 2019:
Annual Report on Progress Against Cancer From the American Society of
Clinical Oncology. \emph{J Clin Oncol} . Apr 1 2019;37(10):834-849.
doi:10.1200/JCO.18.02037

13. Teachey DT, Hunger SP. Predicting relapse risk in childhood acute
lymphoblastic leukaemia. \emph{Br J Haematol} . Sep 2013;162(5):606-20.
doi:10.1111/bjh.12442

14. Bhojwani D, Pui CH. Relapsed childhood acute lymphoblastic
leukaemia. \emph{Lancet Oncol} . May 2013;14(6):e205-17.
doi:10.1016/S1470-2045(12)70580-6

15. Jabbour E, Pui CH, Kantarjian H. Progress and Innovations in the
Management of Adult Acute Lymphoblastic Leukemia. \emph{JAMA Oncol} .
Oct 1 2018;4(10):1413-1420. doi:10.1001/jamaoncol.2018.1915

16. Izraeli S, Vora A, Zwaan CM, Whitlock J. How I treat ALL in Down's
syndrome: pathobiology and management. \emph{Blood} . Jan 2
2014;123(1):35-40. doi:10.1182/blood-2013-07-453480

17. Raanani P, Shpilberg O, Gillis S, et al. Salvage therapy of
refractory and relapsed acute leukemia with high dose mitoxantrone and
high dose cytarabine. \emph{Leuk Res} . Aug 1999;23(8):695-700.
doi:10.1016/s0145-2126(99)00078-8

18. Fuster J. Current approach to relapsed acute lymphoblastic leukemia
in children. Review. \emph{World J Hematol} . August 6 2014;3(3):49-70.
doi:10.5315/wjh.v3.i3.49

19. Parker C, Krishnan S, Hamadeh L, et al. Outcomes of patients with
childhood B-cell precursor acute lymphoblastic leukaemia with late bone
marrow relapses: long-term follow-up of the ALLR3 open-label randomised
trial. \emph{Lancet Haematol} . Apr 2019;6(4):e204-e216.
doi:10.1016/S2352-3026(19)30003-1

20. Lange B. The management of neoplastic disorders of haematopoiesis in
children with Down's syndrome. \emph{Br J Haematol} . Sep
2000;110(3):512-24. doi:10.1046/j.1365-2141.2000.02027.x

21. Maloney KW, Carroll WL, Carroll AJ, et al. Down syndrome childhood
acute lymphoblastic leukemia has a unique spectrum of sentinel
cytogenetic lesions that influences treatment outcome: a report from the
Children's Oncology Group. \emph{Blood} . Aug 19 2010;116(7):1045-50.
doi:10.1182/blood-2009-07-235291

22. Whitlock JA. Down syndrome and acute lymphoblastic
leukaemia.\emph{Br J Haematol} . Dec 2006;135(5):595-602.
doi:10.1111/j.1365-2141.2006.06337.x

23. Paul S, Rausch CR, Nasnas PE, Kantarjian H, Jabbour EJ. Treatment of
relapsed/refractory acute lymphoblastic leukemia. \emph{Clin Adv Hematol
Oncol} . Mar 2019;17(3):166-175.

24. Bierman HR, Crile DM, Dod KS, et al. Remissions in leukemia of
childhood following acute infectious disease: staphylococcus and
streptococcus, varicella, and feline panleukopenia. \emph{Cancer} . May
1953;6(3):591-605.
doi:10.1002/1097-0142(195305)6:3\textless{}591::aid-cncr2820060317\textgreater{}3.0.co;2-m

25. Lynggaard LS, Marquart HV, Kjeldsen E, Madsen HO, Hasle H. Acute
Lymphoblastic Leukemia Presenting With Pancytopenia Followed by a
14-Month-Long Period of Transient Remission Possibly Supporting the
Adrenal Hypothesis of Leukemogenesis. \emph{J Pediatr Hematol Oncol} .
Nov 2016;38(8):e271-e273. doi:10.1097/MPH.0000000000000648

26. Jimemez C, Ribera JM, Abad E, et al. Increased serum tumour necrosis
factor during transient remission in acute leukaemia. \emph{Lancet} .
Jun 19 1993;341(8860):1600. doi:10.1016/0140-6736(93)90739-4

27. Musto P, D'Arena G, Melillo L, et al. Spontaneous remission in acute
myeloid leukaemia: a role for endogenous production of tumour necrosis
factor and interleukin-2? \emph{Br J Haematol} . Aug 1994;87(4):879-80.
doi:10.1111/j.1365-2141.1994.tb06761.x

28. Helbig D, Quesada AE, Xiao W, Roshal M, Tallman MS, Knorr DA.
Spontaneous Remission in a Patient With Acute Myeloid Leukemia Leading
to Undetectable Minimal Residual Disease. \emph{J Hematol} . Apr
2020;9(1-2):18-22. doi:10.14740/jh606

29. Rashidi A, Fisher SI. Spontaneous remission of acute myeloid
leukemia. \emph{Leuk Lymphoma} . Jun 2015;56(6):1727-34.
doi:10.3109/10428194.2014.970545

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