\documentclass[10pt]{article}

\usepackage{fullpage}
\usepackage{setspace}
\usepackage{parskip}
\usepackage{titlesec}
\usepackage[section]{placeins}
\usepackage{xcolor}
\usepackage{breakcites}
\usepackage{lineno}
\usepackage{hyphenat}





\PassOptionsToPackage{hyphens}{url}
\usepackage[colorlinks = true,
            linkcolor = blue,
            urlcolor  = blue,
            citecolor = blue,
            anchorcolor = blue]{hyperref}
\usepackage{etoolbox}
\makeatletter
\patchcmd\@combinedblfloats{\box\@outputbox}{\unvbox\@outputbox}{}{%
  \errmessage{\noexpand\@combinedblfloats could not be patched}%
}%
\makeatother


\usepackage{natbib}




\renewenvironment{abstract}
  {{\bfseries\noindent{\abstractname}\par\nobreak}\footnotesize}
  {\bigskip}

\titlespacing{\section}{0pt}{*3}{*1}
\titlespacing{\subsection}{0pt}{*2}{*0.5}
\titlespacing{\subsubsection}{0pt}{*1.5}{0pt}


\usepackage{authblk}


\usepackage{graphicx}
\usepackage[space]{grffile}
\usepackage{latexsym}
\usepackage{textcomp}
\usepackage{longtable}
\usepackage{tabulary}
\usepackage{booktabs,array,multirow}
\usepackage{amsfonts,amsmath,amssymb}
\providecommand\citet{\cite}
\providecommand\citep{\cite}
\providecommand\citealt{\cite}
% You can conditionalize code for latexml or normal latex using this.
\newif\iflatexml\latexmlfalse
\providecommand{\tightlist}{\setlength{\itemsep}{0pt}\setlength{\parskip}{0pt}}%

\AtBeginDocument{\DeclareGraphicsExtensions{.pdf,.PDF,.eps,.EPS,.png,.PNG,.tif,.TIF,.jpg,.JPG,.jpeg,.JPEG}}

\usepackage[utf8]{inputenc}
\usepackage[greek,english]{babel}



\usepackage{float}








\begin{document}

\title{Myelodysplastic Syndrome with Excess of Blasts - Long Term Partial
Remission with Low Dose Prednisone, G-CSF and Epoetin Alfa}



\author[1]{Anwarul Islam}%
\affil[1]{Buffalo General Medical Center}%


\vspace{-1em}



  
  \date{May 08, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
We have used low-dose prednisone, in conjunction with granulocyte,
colony-stimulating factor (G-CSF) and erythropoietin, to treat an
elderly patient with myelodysplastic syndrome (MDS) with an excess of
blasts. Our findings indicate that such treatment is safe and may be
effective in the long term survival of patients with high-risk MDS.%
\end{abstract}%



\sloppy


Myelodysplastic Syndrome with Excess of Blasts - Long Term Partial
Remission with Low Dose Prednisone, G-CSF and Epoetin Alfa

Anwarul Islam, M.D., Ph.D., FRCPath, FACP

Clinical Associate Professor of Medicine

Division of Hematology/Oncology

Department of Medicine

Buffalo General Hospital, Room E 318

Buffalo, New York 14203

Tel: 716-859-2360

E-mail: aislam@buffalo.edu

ABSTRACT

We have used low-dose prednisone, in conjunction with granulocyte,
colony-stimulating factor (G-CSF) and erythropoietin, to treat an
elderly patient with myelodysplastic syndrome (MDS) with an excess of
blasts. Our findings indicate that such treatment is safe and may be
effective in the long term survival of patients with high-risk MDS.

Key clinical message: Currently, most patients with high risk MDS are
treated with 5-azacitidine or decitabine. These agents are not free of
toxicity. Our treatment is safe, devoid of toxicity, and foster improved
quality of life. There is reduced infection rate, red cell transfusion
independence and little or no requirement of platelet infusion.

INTRODUCTION

Myelodysplastic syndromes (MDS) are a diverse group of hematological
disorders that affect the blood and bone marrow (1). Different types of
medications have been tried in MDS, however, no effective treatment has
yet been established. Currently, most patients with high-risk MDS are
treated with low-intensity regimens that are based on hypomethylating
agents (HMAs) such as 5- azacitidine or decitabine (2). However, these
chemotherapeutic agents are not free of toxicity. Across azacitidine and
decitabine studies, approximately 50\% of patients develop Common
Toxicity Criteria (CTC) grade 3 or 4 cytopenias (3,4), particularly
during the first treatment cycle, necessitating intensive transfusion
support, close monitoring, and placing patients at increased risk of
febrile neutropenia episodes.

We have treated a newly diagnosed elderly patient with high-risk MDS
with a combination of granulocyte-colony-stimulating factor (G-CSF),
low-dose prednisone and, recombinant erythropoietin (EPO). The rationale
of such treatment was that this combination may induce differentiation
of the immature, myeloid and erythroid precursor cells, inhibit
proliferation of the blast cells, and potentially increase or stabilize
the platelet count. Another logic behind this protocol was that this
treatment may also improve the circulating neutrophil count, prevent
serious infections, and avoid the undesirable effects of chemotherapy,
thus improving the quality of life.

Our patient continued to demonstrate positive and satisfactory results
14 months after the therapy was started. The patient went into and
remained in stable, continuous partial remission. His circulating
neutrophil count increased and was generally within normal limits, while
the hemoglobin level is maintained at \textasciitilde{} 8 g/dL without a
need for blood transfusion. The platelet count has remained low
(\textasciitilde{} 40,000/\selectlanguage{greek}μ\selectlanguage{english}L) but was stable and required no platelet
transfusions. Occasional minor elevations of the neutrophil count (up to
15,000/\selectlanguage{greek}µ\selectlanguage{english}L) were treated with diminished allocations of G-CSF. The
peripheral blood smears continued to show a small number (1-4\%) of
blasts and blast-like cells and morphologic features of myelodysplasia
in all three cell lines. The patient's response was slow, to begin with
but had been sustained over an extended period of time. Unfortunately,
he contracted Covid-19 infection and died 10 days later, despite
adequate treatment, including Covid-19 protocol, which involved
dexamethasone, remdesivir and, convalescent plasma.

CASE REPORT

The patient, a 75-years-old white male with a past medical history
significant for hypertension, chronic obstructive pulmonary disease, and
hyperlipidemia, was brought to the emergency room (ER) with a history of
syncopal attack. On physical examination, the patient was noted to be
anemic, but he was not in acute distress. There was no jaundice,
cyanosis, or edema. His abdomen was soft and non-tender. Bowel sounds
were heard. The liver, spleen, and kidneys were not palpable. There was
no palpable lymphadenopathy. Heart sounds S1 and S2 were identifiable,
along with a soft ejection systolic murmur. The chest was clear to
auscultation. His vital signs were stable --blood pressure 125/70 mm Hg,
pulse 72 pm; respiration 18 pm, and temperature
97.6\textsuperscript{*}F.

Laboratory investigations revealed WBC 0.9 x 10\textsuperscript{9}/L,
hemoglobin 8.9 g/dL with normal MCV, and MCH, and a platelet count of 92
x 10\textsuperscript{9}/L. A manual differential count of his peripheral
blood smear revealed 47.0\% neutrophils, 46.0\% lymphocytes, 1\% bands,
2\% monocytes, 1\% basophils, 1\% blasts (Figure 1A), and 2\% blast-like
cells (Figure 1B). There were 10 nucleated RBCs per 100 WBC (Figure 1C).
The peripheral blood smear revealed hypogranularity and hypolobation
(pseudo-Pelger-Huet anomaly) of neutrophils (Figure 1D), multinuclear
(Figure 1E) and bizarre nuclear forms (Figure 1F). Red cells showed
marked anisocytosis, poikilocytosis, dimorphic picture, presence of
ovalocytes and macro-ovalocytes (Figure 2), and marked basophilic
stippling (Figure 2 inset). The peripheral blood smear also displayed
platelet anisocytosis and giant platelets (Figure 2). His serum iron
level was normal at 70\selectlanguage{greek}μ\selectlanguage{english}g/dL (normal range 45-182), the total iron
binding capacity was normal at 374\selectlanguage{greek}μ\selectlanguage{english}g (normal range 261-478) and the
percent saturation was slightly low at 19\% (normal range 20-50). His
reticulocyte count was raised at 7.5 \% (normal range 0.5-1.5\%), The
LDH was raised at 405 (normal range 105-210 U/l). His B12 (390 pg/ml)
and folic acid (15.0 ng/ml) levels were also within normal limits. His
complete metabolic profile was mostly normal, except for total
bilirubin, which was slightly increased at 2.3 mg/dL (normal range
0.3-1.0 mg/dL) and glucose was slightly raised at 151 mg/dL (normal
range 74-100). The routine urine analysis was negative.

Because of severe neutropenia, low hemoglobin level and abnormal
cytologic findings in the peripheral blood smear, hematological
malignancy was suspected and the patient was admitted for further
evaluation, diagnosis and management. Soon after his admission to the
hospital, the patient underwent a bone marrow examination, which
revealed a slightly hypercellular (\textasciitilde{}60\%) bone marrow
(Figure 3) with the increased number of blast cells (12\%) (Figure 4)
and marked dysplastic changes in all three cell lineages (Figure 5-7).
There was marked basophilic stippling, but no ring sideroblasts were
seen. The bone marrow biopsy section revealed focal clusters of immature
myeloid precursor cells (Figure 8).

Flow cytometry studies of the peripheral blood sample revealed an
increased blast cell population 2\% of the events. The blast population
was positive for dim CD45, CD34, CD117, and HLA-DR, while negative for
CD13, CD33, CD14, CD15. The immunophenotype was compatible with a
myeloblast. The granulocytes were slightly decreased and consisted
mostly of mature-appearing granulocytes. No clonal B-cell or atypical
T-cell population was detected.

Flow cytometry studies of the bone marrow aspirate sample revealed an
increased population of cells that were positive for dim CD45, CD34,
CD117, HLA-DR, and dim (CD10 (subset), while negative for CD13, CD33,
CD14, CD15, B-and T-cell markers. No clonal B-cell or atypical T-cell
population was detected (Figure 9).

Cytogenetic analysis of a 24-hour unstimulated bone marrow culture
demonstrated an abnormal male karyotype. Of the 20 mitosis analyzed, one
was normal and 19 showed an abnormal karyotype with an extra chromosome
(trisomy 8) (Figure 10). FISH analysis was positive for trisomy 8 but
negative for RUNX1/RUNX1T1, CBFB/MYTH11, BCR/ABL, MECOM, KMT2A
rearrangement, and MONOSOMY 5 (DELETION OF 5Q), MONOSOMY 7 (DELETION OF
7Q), MONOSOMY 20 (DELETION OF 20Q), ATM (DELETION OF TP53) or 13Q14
deletion. Molecular studies for FLT3, IDH1, IDH2 and TP53 were negative.
The patient was diagnosed to have high-risk MDS, which was determined by
the age, cytopenias, percentage of blasts in the marrow and abnormal
cytogenetic profile (trisomy 8).

Because of the patient's age (75 years) and a diagnosis of MDS with
excess of blasts (high risk), the patient was referred to hospice care.
However, the patient's family declined this option and requested a
treatment that did not involve chemotherapy. At this point, the patient
was started on low-dose prednisone 20 mg orally daily, G-CSF
(filgrastim) 300\selectlanguage{greek}μ\selectlanguage{english}g subcutaneously three times a week (Monday, Wednesday
and Friday) and epoetin (procrit) 30,000 units subcutaneously once a
week. The patient did not receive any other cytokines or chemotherapy.
Prednisone was gradually tapered and was reduced to 5 mg orally daily
for the last 6 months, G-CSF was reduced to 300 \selectlanguage{greek}μ\selectlanguage{english}g once a week; and
epoetin was reduced to 30,000 units once every two weeks for the last
four months.

Within two weeks of the start of the cited treatment, his circulating
neutrophil count began to increase. The hemoglobin concentration and
platelet count remained low (Hb \textasciitilde{}8 g/dL, platelet
\textasciitilde{} 40-60,000/\selectlanguage{greek}μ\selectlanguage{english}L) but stable and did not require RBC or
platelet transfusion. The peripheral blood smear continued to show a
small number (2-4\%) of blast and blast-like cells but no overt signs of
leukemic transformation. As stated earlier the patient contracted
Covid-19 infection and expired soon thereafter.

DISCUSSION

The ideal therapeutic approach for older (age [?] 65 years) patients with
MDS, particularly high-risk groups of patients, is not known. Although
allogeneic hematopoietic stem-cell transplantation can induce long-term
remission in patients with MDS (5-8), such therapy is not applicable for
most patients, since the median age at diagnosis usually exceeds 70
years (9) as is in the case under discussion. Challenges facing current
standard-of-care therapies for high-risk MDS include poor overall
survival, limited duration of response, and singular mechanistic action
(3,10,11). Responses achieved with currently available treatment are
often less than one year of duration (11) and these therapies focus on
either decreasing leukemic proliferation or limiting immune activation
(10,12). Many high-risk MDS patients require repeated blood transfusions
and are often at risk for serious infections and hospitalization.

In general high-risk elderly patients are treated with demethylating
agents such as 5-azacitidine or decitabine since the publication of an
article that demonstrated treatment with demethylating agent results in
superior remission rates, as compared with supportive care, and in some
cases a delay in blastic transformation (13). In a recent randomized
study that compared azacitidine treatment with conventional care in
patients with high-risk disease, the median survival was 24.5 months in
the azacitidine group, as compared with 15.0 months in the conventional
care group (3). However, treatment for elderly patients with high-risk
MDS with demethylating agents is not free of toxicity and
treatment-related mortality can be quite high (3,4,14). Furthermore,
once a drug fails in one of these patients, further treatment options
are limited and median survival is less than six months (15).

MDS has been considered a malignant condition and consequently treatment
of this condition has been chemotherapy, except for a few studies where
G-CSF and erythropoietin were tried in patients with low risk disease
and minimal transfusion-dependence (16,17). We took a different
approach, believing that perhaps this condition is a manifestation of an
underlying disorder (18) rather than a malignant disorder. Accordingly,
we treated our patient not with chemotherapy but with a combination of
prednisone, and myeloid and erythroid-stimulating factors such as G-CSF
and EPO. We believe this is the first-reported high-risk MDS patient who
was treated in this combination. It achieved excellent results. We
believe this observation merits further evaluation and a prospective
trial. However, as we have reported earlier (18), the diagnosis of MDS
is not uniform and considerable variations exist among the MDS patients
as well as diagnosticians. This disease is often misclassified as
evidenced by the fact that over 50\% of patients in certain registries
were considered ``MDS -- unclassifiable'' (9,19). When bone marrow
biopsies are not studied in parallel with bone marrow aspiration during
the investigation and diagnosis of MDS, the abnormal localization of
blast cells may be missed and as a result, high-grade MDS may be
misdiagnosed as low or intermediate-risk thus jeopardizing the correct
stratification of this disease and thereby influencing the prognostic
outcome. As a result, one has to be mindful of comparing apples and
oranges in the setting of the same or similar treatment.

References

1.Snowden J A, \textbf{O} 'Connell S, Hawkins J, et al. Haematological
cancers: improving outcomes. A summary of updated NICE service guidance
in relation to Specialist Integrated Haematological Malignancy
Diagnostic Services (SIHMDS) J Clin Pathol 2017;70:461-468 doi:
10.1136/jclinpath-2016-204029

2.Favor M G, Griffiths E A, Thota S. Current state of myelodysplastic
syndromes: standard treatment practices and therapeutic advances. J Clin
Pathways 2019;5:43-47

3.Fenaux P, Mufti G J, Hellstrom-Lindberg E, et al. International Vidaza
High-Ris MDS survival Study Group. Efficacy of azacitidine compared with
that of conventional care regimens in the treatment of higher-risk,
myelodysplastic syndrome: a randomized, open-label, phase III study.
Lancet Oncol. 2009;10: 223-232.

4. Lubbert M, Suciu S, Baila L, et al. Low-dose decitabine versus best
supportive care in elderly patients with intermediate- or high-risk
myelodysplastic syndrome (MDS) ineligible for intensive chemotherapy:
final results of the randomized phase III study of the European
Organization for Research and Treatment of Cancer Leukemia Group and the
German MDS Study Group. J Clin Oncol. 2011; 29: 1987-1996

5. Chang C, Storer B E, Scott B L, et al., Hematopoietic cell
transplantation in patients with myelodysplastic syndromes or acute
myeloid leukemia arising from myelodysplastic syndrome: similar outcomes
in patients with de novo disease and disease following prior therapy or
antecedent hematologic disorders, Blood 2007;110:1379-1387.

6. Warlick E D, Cioc A, Defore T, et al. , allogeneic stem cell
transplantation for adults with myelodysplastic syndromes: importance of
breed transplant disease burden. Biol Blood Marrow Transplant
2009;15:30-38.

7. Alessandrino E P, Porta M G, Malcovati L, et al. , on behalf of
Gruppo Italiano Trapianto di Midollo Osseo (GITMO). Optimal timing of
allogeneic hematopoietic stem cell transplantation in patients with
myelodysplastic syndrome. Am J Hematol 2013.

8. Platzbecker U, Schetelig J, Finke J, et al., German MDS study;
Cooperative Transplant Study Ggroup; Fred Hutchinson Cancer Research
Center: group Francophone des Myelodysplasies. Allogeneic hematopoietic
cell transplantation in patients age 60-70 years with de novo high-risk
myelodysplastic syndrome or secondary acute myelogenous leukemia:
comparison with patients lacking donors who received azacitidine. Biol
Blood Marrow Transplant. 2012; 18 1415-1421.

9. Rollison D E, Howlader N, Smith, M T, et el. Epidemiology of
myelodysplastic syndromes and chronic myeloproliferative disorders in
the United States, 2001-2004, using data from NAACCR and SEER programs.
Blood. 2008;112:45-52.

10. Kadia T M, Jabbour E, Kantarjian H. Failure of hypomethylating
agent- based therapy in myelodysplastic syndromes. Semin Oncol. 2011;
38: 682 -- 692.

11. Platzbecker U. treatment of MDS. Blood. 2019;133:1096-1107

12. Kordasti S Y, Ingram W, Hayden J, et al. CD4+CD25high
Foxp3+regulatory cells in myelodysplastic syndrome (MDS) Blood.
2007;110:847-850.

13. Silverman L R, Demakos E P, Peterson B L, et al. Randomized
controlled trial of azacitidine in patients with the myelodysplastic
syndrome: a study of the Cancer and Leukemia Group B. J Clin Oncol
2002:20:2429-2440.

14. Gao C, Wang J, Li Y, et al. Incidence and risk of hematologic
toxicities with hypomethylating agents in the treatment of
myelodysplastic syndromes and acute myeloid leukemia. A systematic
review and meta-analysis. Medicine 2018; 97: 1-13

15. Sekeres M A, and Cutler C. How we treat higher- risk myelodysplastic
syndromes. Blood;123: 829-836

16. Hussain I S. Myelodysplastic syndromes in the elderly: role of
growth factors in management. Leukemia Research. 1996; 20: 203-219.

17. Jadersten M, Malcovati L, Dybedal I, et al. Erythropoietin, and
granulocyte-colony stimulating factor treatment associated with improved
survival in myelodysplastic syndrome. J Clin Oncol. 2008; 26: 3607-3613.

18. Islam A. Myelodysplastic Syndromes: A Diagnostic and Therapeutic
Conundrum. Ann Hematol Oncol. 2020; 7(8): 1318.

19. Cogle C R, Craig B M, Rollison D E, et.al. Incidence of the
myelodysplastic syndromes using a novel claims-based algorithm: highly
number of uncaptured cases by cancer registries. Blood. 2011;
117:7121-7125.

Legends:

Figure 1 (A) A myeloblast (note a prominent nucleolus), (B) a blast-like
cell (a similar cell as A but note absence of nucleolus, (C) two
nucleated red blood cells (D) bilobed and `spectacle' forms (note
hypo-granulation), (E) multi nuclear and (F) bizarre forms.

Figure 2. A peripheral blood smear showing dimorphic blood picture along
with anisocytosis, poikilocytosis and presence of ovalocytes,
macro-ovalocytes. Note platelet anisocytosis and giant platelets. The
inset (lower right hand corner) shows a red blood cell with basophilic
stippling.

Figure 3. Bone marrow biopsy section showing slightly hypercellular
marrow.

Figure 4. Bone marrow aspirate smear showing a myeloblast. Note
prominent nucleoli.

Figure 5. Bone marrow aspirate smear showing dysplastic changes in
erythroid precursors. (A)- inter-cytoplasmic bridging, (B) - nuclear
budding, (C)-nuclear cytoplasmic maturation asynchrony.

Figure 6. Bone marrow aspirate smear showing dysplastic changes in
granuloid precursors. A- pseudo Pelger-Huet anomaly, B- bizarre nuclei,
C- a giant metamyelocyte.

Figure 7. Dysmegakaryopoiesis: multi nuclear megakaryocytes, top row,
bone marrow aspirate smear. Bottom row: mono, bi and multi-nucleated
megakaryocytes-bone marrow biopsy section.

Figure 8. Bone marrow biopsy section demonstrating focal clusters of
immature myeloid precursors (blast cells) which can be easily identified
by the presence of nucleolus and nucleoli. Two cells in mitosis (arrows)
can be seen.

Figure 9. Flow cytometry results of bone marrow aspirate obtained at
diagnosis: cluster analysis of blasts using CD45/SSC. Pink: blasts;
green: lymphocytes; blue: granulocytes; red: erythroid precursors and
debris and orange; monocytes.

Figure 10. Fluorescent in situ hybridization of bone marrow cells
identify an abnormal karyotype with an extra chromosome 8 (trisomy 8).\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1/Figure-1}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-2/Figure-2}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-3/Figure-3}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-4/Figure-4}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-5/Figure-5}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-6/Figure-6}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-7/Figure-7}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-10/Figure-10}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-9/Figure-9}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-8/Figure-8}

\end{center}
\end{figure}

\selectlanguage{english}
\FloatBarrier
\end{document}

