Shinshu Med J, 71⑹：393～402, 2023

Dual-alkylator Conditioning Regimen with Busulfan and Melphalan
for Bone Marrow Allogeneic Hematopoietic Stem Cell Transplantationin Patients with Myelofibrosis : The Results of a Retrospective Studyat a Single Institution in Japan
Mariko Asai1）, Shuji Matsuzawa1）, Fumihiro Kawakami1）, Toru Kawakami1）
Kaoko Sakai1）, Sayaka Nishina1）, Hitoshi Sakai1）, Toshiro Ito1）2）
Fumihiro Ishida1）3） and Hideyuki Nakazawa1）＊
1） Department of Hematology and Medical Oncology, Shinshu University School of Medicine
2） Center of Hematology, Matsumoto Medical Center3） Department of Biomedical Laboratory Sciences, Shinshu University School of Medicine

Myelofibrosis (MF) is a myeloproliferative neoplasm associated with significant morbidity and mortality, andallogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative approach. While theoptimal conditioning regimen before allo-HSCT for MF patients remains to be determined, recent studies havesuggested that a thiotepa-busulfan-containing dual-alkylator regimen, FBT regimen, may be associated withfavorable outcomes. In Japan, however, thiotepa is not indicated for MF. Here we describe the results of 6 casesof MF treated with melphalan-busulfan containing dual-alkylator regimen, FBM regimen, followed by their firstallo-HSCT at a single institution. Neutrophil and platelet engraftment was achieved in all patients. And a full donor
chimerism was confirmed in all patients at ＋30 days after allo-HSCT. The relatively small size and short obser­
vation period of our study make it difficult to draw a definitive conclusion ; however, our results suggest that a dualalkylator regimen of FBM may be a candidate for an conditioning for allo-HSCT for MF, which should be verified
with a large cohort of patients. Shinshu Med J 71 : 393―402, 2023
(Received for publication May 12, 2023 ; accepted in revised form August 21, 2023)
Key words : myelofibrosis, allogeneic stem cell transplantation, conditioning regimen, dual alkylator
geneic hematopoietic stem cell transplantation (allo-

Ⅰ Introduction

HSCT) remains the only curative procedure for pa­

Myelofibrosis (MF) is a Philadelphia chromosome1）

negative myeloproliferative neoplasm (MPN) . It cantients with MF, even in the era of Janus kinase (JAK)inhibitors2）6）7）.

present as a primary MF or a secondary MF to poly­

Although allo-HSCT may provide a cure for a pa­

cythemia vera (PV) or essential thrombocythemia

tient with MF, however, the rarity of the disease also

(ET), and characterized by a progressive risk of blood

precludes large-scale prospective control trials totransfusion dependency due to cytopenia, leukemic

establish a standard approach regarding indication,changes with clonal evolution, and multiple organ

timing, and platform of allo-HSCT, and a tailor-madedamage with extramedullary hematopoiesis

2）-5）. Allo­approach is mandatory to help guide the patients with
MF6）8）. Clinical guides often recommend that patients＊

Corresponding author : Hideyuki Nakazawa
Department of Hematology and Medical Oncology,
Shinshu University School of Medicine, 3-1-1 Asahi,
Matsumoto, Nagano 390-8621, Japan
E-mail : hnaka@shinshu-u.ac.jp

No. 6, 2023

with intermediate- or high-risk MF are eligible forallo-HSCT, if they are medically fit6）9）. Hence, trans­
plant eligibility varies between institutions, but there
has been a steady increase in the number of patients393

Asai・Matsuzawa・Kawakami et al.

world-wide undergoing allo-HSCT as a potentially
4）
10）
11）

curative treatment over the past 15 years

performed at the Department of Hematology, Shinshu
University School of Medicine between 2013 and 2022.

.

However, some patients may be discouraged to

The diagnosis of MF was confirmed in accordance

proceed to allo-HSCT because of the challenges thatwith the WHO Classification Tumours of Haemato­

are characteristic to MF : high risk of engraftment

poietic and Lymphoid Tissues, 4th edition 20171）. Pa­

failure and/or poor graft function, largely due to fi­

tients with secondary myelofibrosis transformed frombrotic changes in the bone marrow and a splenomeg­

other MPNs, i.e. post-PV MF and post-ET MF, were

4）
12）

.

included in the cohort. Patients with bone marrow

The sequestration of transplanted stem cells in the

fibrosis with other underlying non-MPN conditions

enlarged spleen may negatively affect the transplan­(e.g., myelodysplastic syndrome with bone marrow

aly associated extramedullary hematopoiesis of MF

6）
13）
-15）

. Several strate­

fibrosis) were excluded. If a patient underwent multi­

gies have been in practice to mitigate a risk of allo-

ple transplants, only the data obtained during the

HSCT due to splenomegaly in MF patients, including

first allo-HSCT procedure were included in the anal­

surgical removal of the spleen, pre-transplantation

ysis. Relevant clinical data were retrieved from thesplenic eradiation, and administration of JAK inhibi­

patients’ medical records. Disease-based risk scores

tation outcome in MF patients

6）

tor, ruxolitinib . However, an increased risk of devel­

were calculated using three scoring systems : theopment of acute leukemia after splenectomy, a risk of

Dynamic International Prognostic Scoring Systemprolonged pancytopenia and infection after radiation(DIPSS)23）, the DIPSS-plus24）, and the Myelofibrosis

therapy, and a limited durability of JAK inhibitor, re­Secondary to PV and ET (MYSEC-PM)25）. The rele­main to be concerns for each strategy6）. On the othervant data within a month before the first day of ahand, studies suggest that some conditioning regi­

conditioning regimen were applied to each scoringmens may be associated with better engraftment andsystem. A size of the spleen before allo-HSCT was

overall transplant outcomes than those with othermeasured with CT scans and a Kucybala’s index, aregimens, regardless of interventions for splenomeg­

product of the maximal length (Lmax) and the verti­

6）12）. Recently, Bacigalupo and others described

cal hight (Hvert) of the spleen, was calculated forthat a dual-alkylator regimen, containing thiotepa

each patient to represent a volume of the spleen. A

and busulfan (FBT regimen), may improve the trans­

splenomegaly was determined when a Kucybala’s

aly

16）
17）

plantation outcome in MF

index was higher than 115, according to the original.

In Japan, however, FBT regimen is not indicatedfor MF, and another set of dual alkylators has been

literature26）.
Ｂ

Chimerism analysis

frequently used in allo-HSCT for myeloid malignan­

DNAs extracted from the bone marrow, wholecies : a regimen containing melphalan and busulfan

peripheral blood and a CD3-positive fraction of the

18）
-21）

. A favorable engraftment was

peripheral blood, all of which were obtained at ＋1

also described in MF patients treated FBM regimen

month after transplantation, were subjected to a chi­

(FBM regimen)

22）

followed by cord blood transplantation . Hence, wemerism analysis, as previously described27）. Briefly,

herein report a result of a retrospective analysis of

we semi-quantitatively compared the short tandem

bone marrow allo-HSCT with FBM regimen in pa­

repeats between the donor-derived DNA and thetients with MF at our institution over the past ten

patient-derived DNA, which had been identified inyears.

advance to distinguish them prior to transplantation,
Ⅱ

Ａ

Patients and Methods

Patients
A list of patients with MF was extracted from thedataset of the recipients to whom allo-HSCT was394

using a polymerase chain reaction-based method.
Mixed chimerism was defined as the presence of ≥5 ％ recipient-derived DNA in the sample28）.
Ｃ

Statistical analysis

The primary endpoint was neutrophil engraftment.
Shinshu Med J

l. 71

Dual-alkylator conditioning for MF

The day of neutrophil engraftment was defined asⅢ

the first day of three consecutive days with an abso­lute neutrophil count ≥ 0.5×103/μL by ＋28 days afterＡ

Results

Patients

transplantation. Delayed engraftment was defined as

A total of 9 recipients of allo-HSCT for MF wasneutrophil engraftment between ＋28 days and ＋42

identified during the study period. One of the patientsdays after transplantation. Primary graft failure wasunderwent her second allo-HSCT and two patientsdefined as failure to exceed the threshold absoluteused only single alkylator as their conditioning

donor-derived neutrophil count by day ＋43 after

regimen ; thus, the data from six transplants weretransplantation.

included in this analysis. The characteristics of theSecondary endpoints included platelet engraftment.
The day of platelet engraftment was defined as the4enrolled patients are summarized in Table 1.
There were 2 males and 4 females with a medianfirst day with an absolute platelet count of ≥ 2×10 /age (range) of 63 (31-69) years at the time of allo-

μL, maintained for 3 days, without blood transfusion

HSCT. Their diagnoses were primary MF (n＝1),

support in the previous 7 days after transplantation.

post-PV MF (n＝1) and post-ET MF (n＝4). Driver

Donor chimerism at 1 month after the transplantation,

mutations were detected in all the patients : JAK2

clinical status including GVHD and residual bone

V617F (n＝5) or CALR 52bp del (n＝1). Chromosomal

marrow fibrosis after allo-HSCT, platelet recovery

abnormalities were evaluated in all patients and4of ≥ 5×10 /μL without transfusion support, 1-year

an abnormal karyotype was found in 3 patients. Two

overall survival (OS), and 1-year event-free survivalof the abnormalities included a trisomy 9, and one(EFS) were also evaluated. OS was defined as theof the patients had a complex karyotype, definedtime from the date of allo-HSCT to the date of deathas harboring 3 or more abnormal karyotypes30）. The

from any cause, and EFS was defined as the timedisease risks were also summarized in Table 1 ; thefrom the date of allo-HSCT to the date of events,

DIPSS were either int-1 risk (n＝2) or int-2 risk (n＝including graft failure, disease progression with leu­

3) ; the DIPSS-plus were either int-1 risk (n＝1), int-

kemic transformation, a veno-occlusive disease/sinu­

2 risk (n＝4), or high risk (n＝1) ; and MYSEC-PM

soidal obstruction syndrome (VOD/SOS), and death

were either low risk (n＝2), int-1 risk (n＝2), or int-2

from any cause.

risk (n＝1). Five of the six patients had splenomega­

All statistical analyses were performed with EZRly, four of which were palpable below the left subcos­

version 1.61 (available at Saitama Medical Center, Jichi

tal margin, at the time of allo-HSCT. One of the five

Medical University, Saitama, Japan [https://www.

patients had splenomegaly of 11cm below the sub­jichi.ac.jp/saitama-sct/SaitamaHP.files/statmedEN.

costal margin despite of ruxolitinib treatment. The

html]), which is a graphical user interface for R (The R

other patient (UPN#3) had received a splenectomy 6Foundation for Statistical Computing, Vienna, Austria).

months before allo-HSCT because he had an intra-More precisely, it is a modified version of R commander

splenic nodule, 7cm in diameter with a high uptake

designed to add statistical functions frequently used inon 18F-FDG positron emission tomography, whichbiostatistics29）.

might have been contraindicative to an organ trans­Ｄplantation if it were a metastatic lesion of another

Ethical considerations
This study was conducted with approval by the in­malignancy. It was, however, pathologically deter­

stitutional review board of Shinshu University School

mined to be an extramedullary hematopoietic area ofof Medicine (approval number #5749, approval dateMF, and he was eventually considered to be indicat­

stFebruary 1 , 2023). Patients who did not agree to be

ed to allo-HSCT. Two patients with an int-1 risk

included in the present study were excluded fromwith the DIPSS had increased blasts (＞1 ％) in their

the list using an opt-out method.

peripheral blood in repeated manual measurements(2-5 ％ in UPN #2 and 1-7 ％ in UPN #5). The per­No. 6, 2023

395

396

61

69

31

69

57

2

3

4

5

6

F

F

F

M

F

M

post-ET MF

post-PV MF

post-ET MF

post-ET MF

post-ET MF

primary MF

diagnosis

MF-3

MF-2

MF-2

MF-1

MF-3

MF-2

BM
fibrosis

46,XY
47,XX,add(6)(p21),＋9,
add(16)(p11.2) / 46,XX
46,XY
46,XX
46,XX,del(20)(q11.2q13.3)/ 46,XX
48,XX,＋9,＋21 / 46,XX

JAK2
(NA)
JAK2
(70.9)
JAK2(64.3)
CALR
(NA)
JAK2
(91.3)
JAK2(68.5)
int-1

int-2

int-2

int-1

int-2

int-2

driver mutation
chromosomal abnormality DIPSS#(allele burden ％)Patients’ demography

int-2

int-2

int-2

int-1

high

int-2

DIPSSplus#

low

int-2

low

int-2

int-1

int-1

MYSECPM#

6.5 ㎝

not palpable

4㎝

splenectomized＊＊

11cm

11cm

subcostal
splenomegaly
palpable before
HSCT

Before allo-HSCT

0

0

0

1

0

0

－

－

－

－

－

＋

PS RuxShinshu Med J

BM

BM

BM

BM

BM

BM

1

2

3

4

5

6

unrelatedunrelatedunrelatedunrelatedunrelatedunrelated

relationshipof donor

＋/＋

－/＋

－/＋

＋/＋

－/＋

＋/＋

CMV status(donor/recipient)

allele HLA-DR

matchedmatchedserum HLA-DR

allele HLA-B

serum HLA-DR

HLA disparity(HGV direction)

allele HLA-DR

matchedmatchedmatchedallele HLA-B

serum HLA-DR

HLA disparity(GVH direction)

Flu-Bu-Mel

Flu-Bu-Mel

Flu-Bu-Mel

Flu-Bu-Mel

Flu-Bu-Mel

Flu-Bu-Mel

Conditioning
regimen

Allo-HSCT with dual alkylators in patients with MF

MAC

RIC

MAC

MAC

MAC

RIC

intensity

＋

－

－

－

＋

＋

ATG

major

major

major

minor

minor

minor

ABO mismatch

2314

1210

2656

0

4769

2693

Kucybala’s index(Lmax) x (H vert)

Abbreviations ; allo-HSCT, allogeneic stem cell transplantation ; MF, myelofibrosis ; HVG direction, host-versus-graft direction ; GVH direction, graft-versus-host direction ; CB,
cord blood ; BM, bone marrow ; ATG, anti-thymocyte immunoglobulin, Flu, fludarabine ; Mel, melphalan ; Bu, busulfan ; TBI, total body irradiation ;Stem Cell
SourceUPN#

Table 2The spleen, palpable for 2.5cm subcostal margin, was resected 6 months before allo-HSCT. # Risk scores were calculated within a month before allo-HSCT.

＊＊64

age atallo- sex
HSCT

1

UPN#

At diagnosis

Table 1

Asai・Matsuzawa・Kawakami et al.

l. 71

Dual-alkylator conditioning for MF

formance status at the time of allo-HSCT was 0 or 1

GVHD prophylaxis or treatment. Anti-epileptic agentsin all patients.

were administered prophylactically along with busul­

Ｂ

Transplantation characteristics (Table 2)

fan.

All transplantation procedures were performed at

Ｃ

Outcomes of transplantation

the Department of Hematology, Shinshu University

Neutrophil engraftment was obtained in 6 of the 6

Hospital. A conditioning was uniformly an FBM

patients (100 ％) with the median (range) time to neu­

regimen ; intravenous busulfan (Bu ; 3.2 mg/kg) on

trophil engraftment was ＋20 (19-31) days (Table 3).

2

One of them showed a delayed neutrophil engraft­2

and fludarabine (Flu ; 30 mg/m ) on day -7 to -2.

ment (UPN#2). Platelet recovery of ≥ 2×104/μL was

Busulfan was reduced to a half-dose when a reduced

also observed in all the patients ; the patient with aintensity regimen was preferred to a myeloablative

delayed neutrophil engraftment required about 10

one for patients who were older than 65 years old andmonths to achieve the platelet engraftment. The me­less fit.

dian (range) days to platelet engraftment was ＋40

day -7 to -4, melphalan (40 mg/m ) on day -3 and -2,

The donors were unrelated bone marrow in all(29-292). All patients achieved platelet recovery of ≥cases. The donor-recipient pairs of HLA typing were

5×104/μL but required even longer period of time ;either one-locus serum mismatched (n＝2), one-locus

the median (range) days was 51 (34-565). Chimerism

allele mismatched (n＝2), or 8/8 matched (n＝2) inanalyses at ＋30 days after transplantation showed

the HVG direction. In the GVH direction, the donor-

that full donor chimerism was observed in all therecipient pairs were either one-locus serum mis­patients who received a dual-alkylator conditioning

matched (n＝1), one-locus allele mismatched (n＝2), of

regimen. Acute GVHD, grade II, was observed in one

fully matched (n＝3). The ABO blood types were

patient. SOS/VOD event was not found in this cohort.

mismatched in a major direction (n＝3) and in a minor

Splenomegaly was significantly ameliorated in all the

direction (n＝3).

cases with enlarged spleen at the time of transplan­

A GVHD prophylaxis was a combination of a calci­

tation (Table 3, Fig. 1). The bone marrow biopsy wasneurin inhibitor and short-term methotrexate. Rabbit

performed in five of the six patients between 3 and2anti-thymocyte immunoglobulin (ATG) 2 mg/m was

12 months after allo-HSCT ; pathological improve­administered on day -1 if severe GVHD was antici­

ment was observed in all the subjects, including

pated because of HLA mismatch between the donor

disappearance of fibrotic changes in three of themand recipient.

(Table 3, Fig. 2). The median (range) period during

Prophylaxis for infections included levofloxacin (500which blood transfusion was required was 169 (37-mg, daily) from day -7 until neutrophil engraftment,

278) days for red blood cell product and 36 (27-278)

acyclovir (200 mg, twice daily) and fluconazole (200days for platelet product. All the patients did not

mg, daily) from day -7 until a month after the cessa­

require blood transfusion a year after allo-HSCT. Alltion of GVHD prophylaxis or treatment. Fluconazole

the patients are alive with the median (range) period

was replaced by voriconazole (200 mg, twice daily) orof observation of 25.5 (11-54) months from allo-

posaconazole (300 mg, twice daily) when a renovative

HSCT. The estimated 1-year OS was 100 ％.

construction was started at different wards in thesame hospital building in August 2021. Since leter­

Ⅳ

Discussion

movir was approved in 2018, it was administered at a

The present study provides the result of a retro­dose of 480 mg, once daily, for three months from thespective analysis of the consecutive patients who re­initiation of the conditioning regimen. Sulfamethoxaz­ceived a dual alkylator conditioning regimen followedole (400 mg, daily) and trimethoprim (80mg, daily)

by bone marrow allo-HSCT for MF at a single in­were prescribed soon after the day of neutrophil

stitution over the past 10 years. The relatively

engraftment until one month after the cessation ofsmall size of cohort and short observation period of

No. 6, 2023

397

398

our study make it difficult to draw definitive conclu­
sions ; however, our results may suggest several points
that are worth mentioning.
Splenomegaly was often attributed to delayed he­matologic recovery after allo-HSCT in MF in previous
literatures6）. A sequestration of transplanted stem
cells and progeny platelet in the residual enlarged
spleen has been a suggested mechanism. Indeed, aplatelet engraftment was apparently delayed in one of
our patients, UPN#2, who had presented the largest
spleen in size among the cohort. However, neutrophil
and platelet engraftment were eventually achievedin all the patients, while 83 ％ of the patients had sig­
nificant splenomegaly at the time of transplantation(Table 1). Spearman rank-order correlations showedthat there were only weak associations between the
spleen volume at the time of transplantation and thedays required for engraftment of neutrophil (r＝0.334,
p＝0.518) and platelet (r＝0.6, p＝0.242) (Fig. 3). A
favorable result in terms of engraftment in this cohort
was also supported by a full donor chimerism at ＋30
days after allo-HSCT attained in all the subjects. Al­
though a comparative analysis between different con­ditioning regimens is beyond a scope of the present
study, we could speculate that FBM regimen may
have a potential to overcome the negative effect of asplenomegaly and to guarantee an engraftment of
the transplanted donor’s hematopoietic precursors in
MF patients.
The rate of VOD/SOS occurrence after allo-HSCT
was generally described as about 5 to 10 ％ of alloHSCT recipients, and a busulfan-containing condi­
tioning regimen is known to impart a high risk of
VOD/SOS, especially in a high dose regimen or in a
combination with another alkylator31）32）. The rate of
VOD/SOS was described as 3-9 ％ of patients with
MF after another dual alkylator regimen, FBT17）33）.
Our cohort, which a dual alkylator FBM regimen was
was recepient origin.

Abbreviations ; allo-HSCT, allogeneic stem cell transplantation ; MF, myelofibrosis ; GVHD, graft versus host disease ; SOS/VOD, sinusoidal obstruction syndrome/veno-occlusive
disease ; PS, performance statuts ; NA, not available ; ＊An increase of neutrophil was observed, but a chimerism analysis conducted a week later suggested that the engraftment

MF-2
4cm palpable
1
alive
11
negative
44
20
6

no fibrosis
not palpable
1
alive
18
negative35
19
5

biopsy notavailable
2.5cm palpable
1
alive
21
negative
29
20
4

no fibrosis
not applicable
1
alive
30
negative
Grade II
36
21
3

no fibrosis
not palpable
1
alive
43
negative
292
31
2

MF-1
not palpable
1
alive
51
20
1

neutrophil

platelet

-

-

GVHD

negative54

subcostal splenomegalyPSsurvival(months)

BM fibrosis
Clinical Status at Last Observation

allo-HSCT

period from

SOS/VOD
chronic

UPN#

Days from HSCT toEngraftment

acute GVHD

Table 3The Outcome of Allo-HSCT in the 6 consecutive patients with MF

after HSCT

Asai・Matsuzawa・Kawakami et al.

universally adopted to, did not have a case of VOD/
SOS, possibly because our cohort was too small for aclinician to encounter an event when the incidence
rate was up to 10 ％.
Several limitations associated with the present study
warrant mention. We speculated that the favorable
Shinshu Med J

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Dual-alkylator conditioning for MF

Fig. 1 Improvement of splenomegaly after allo-HSCTThe enlarged spleen was significantly ameliorated after allo-HSCT. Abdominal computed tomography scans
before (A) and 3 months after allo-HSCT (B) in UPN#2, as a representative case of splenomegaly in MF patient.
Kucybala’s index was decreased from 4769 to 1932 in 3 months after allo-HSCT in this case.

Fig. 2 Improvement of bone marrow fibrosis after allo-HSCT
The bone marrow biopsy samples of UPN#5, as a representative case of MF, showed pathological improvement ofbone marrow fibrosis (original magnification, ×10 ; Silver stain) ; before (A) and 3 months after allo-HSCT (B). The
fibrosis was improved from MF-2 to MF-1 in 3 months after allo-HSCT. Fig. 2(C) shows longitudinal changes offibrosis ; the vertical axis indicates the gradings of bone marrow fibrosis and each colored line represents a case of MF.
Pathological improvement was observed in all the subjects, including disappearance of fibrotic changes in three cases.

engraftment result of our cohort may possibly be

0.3 per 100 thousand a year and majority of them areassociated with a dual alkylator regimen that we uni­

elderly and thus ineligible for transplant8）. The largest

versally adopted. However, a comparative analysis

cohort study of allo-HSCT for MF in Japan had 224

with a large number of allo-HSCT recipients withcases for 24 years8）. The goal of the present study

MF may be necessary to draw a firm conclusion of

may thus be to summarize the characteristics andsuperiority of one regimen to another. For example,

outcomes of the transplantation for MF at our insti­

more than 500 registry of MF patients may be re­tution in the previous ten years, which should even­quired to show a superiority of one conditioning reg­tually provide a dataset to be referred to in a clinicalimen to another in 1-year overall survival, if we per­comparative study in the future to develop a better

form a cox hazard ratio analysis with a presuppositiontransplantation platform at this institution.

of 10 ％ of event rate and five confounding factors

Besides a conditioning regimen, other factors ofincluded. However, an estimated incidence of MF istransplantation may also be confoundings to analyze

No. 6, 2023

399

Asai・Matsuzawa・Kawakami et al.

Fig. 3 Associations between the spleen volume before transplantation and days required for engraftment
A spleen volume was represented by a product of the maximal length (Lmax) and the vertical hight (Hvert) on theabdominal CT scans, a Kucybala’s index. Spearman’s rank-order correlation coefficient was calculated to analyze
associations between the Kucybala’s indices and the days required for the engraftment of neutrophil (A) and platelet(B). The correlations were weak, implying that neutrophil and platelet engraftment was attained regardless of thesize of the spleen at the time of transplantation.

the outcomes in patients with MF, such as the inten­Ⅴsity of regimens, HLA disparity, GVHD prophylaxis,

Conclusion

degree of BM fibrosis and splenic size at the time of

We retrospectively summarized the transplanta­transplantation, and usage of ruxolitinib before trans­

tion outcomes of all the consecutive cases of MF re­plantation. These factors should have been included

ceiving allo-HSCT after a dual alkylator regimen at a

in a propensity score matching analysis, for example,

single institution. We speculated that a dual-alkylator

with a larger size of cohort to draw a more solid con­regimen of FBM may be a candidate conditioning for

clusion about a role of dual alkylator regimen as abone marrow allo-HSCT in patients with MF, which

conditioning for MF, although the small size of ourneeds to be verified in studies with a large sizedcohort precluded such an analysis. Furthermore, newcohort of patients.

treatment strategies have been recently introduced

Conflict of Interest

to allo-HSCT for MF, such as alternative donors, a
post-transplantation cyclophosphamide as a GVHD
prophylaxis, and a GVHD treatment with ruxolitinib

The authors declare that they have no competinginterests.

and ibrutinib. These novel strategies will also confer
different outcomes of allo-HSCT for MF in near future.
References
1） Swerdlow SH, Campo E, Harris NL, et al : WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues.
Revised 4th Edition, Lyon : International Agency for Research on Cancer, 20172） Kröger N, Giorgino T, Scott BL, et al : Impact of allogeneic stem cell transplantation on survival of patients less than
65 years of age with primary myelofibrosis. Blood 125 : 3347-3350 ; quiz 3364, 20153） Kroger NM, Deeg JH, Olavarria E, et al : Indication and management of allogeneic stem cell transplantation in primary
myelofibrosis. a consensus process by an EBMT/ELN international working group. Leukemia 29 : 2126-2133, 20154） Ali H, Bacigalupo A : 2021 Update on allogeneic hematopoietic stem cell transplant for myelofibrosis : A review of400

Shinshu Med J

l. 71

Dual-alkylator conditioning for MF
current data and applications on risk stratification and management. Am J Hematol 96 : 1532-1538, 2021
5） Sangle N, Cook J, Perkins S, et al : Myelofibrotic transformations of polycythemia vera and essential thrombocythemia
are morphologically, biologically, and prognostically indistinguishable from primary myelofibrosis. Appl Immunohistochem
Mol Morphol 22 : 663-668, 2014
6） Bacigalupo A, Innocenti I, Rossi E, et al : Allogeneic Hemopoietic Stem Cell Transplantation for Myelofibrosis : 2021.
Front Immunol 12 : 637512, 2021
7） Kroger N, Sbianchi G, Sirait T, et al : Impact of prior JAK-inhibitor therapy with ruxolitinib on outcome after
allogeneic hematopoietic stem cell transplantation for myelofibrosis : a study of the CMWP of EBMT. Leukemia 35 :
3551-3560, 2021
8） 赤司浩一，下田和哉，桐戸啓太，他：骨髄線維症

診療の参照ガイド令和４年改訂版（第６版）．In : Mitani K(ed)特発性造血障害疾患の診療の参照ガイド，2023
9） Tefferi A : Primary myelofibrosis : 2019 update on diagnosis, risk-stratification and management. Am J Hematol
93 : 1551-1560, 201810） McLornan D, Szydlo R, Koster L, et al : Myeloablative and Reduced-Intensity Conditioned Allogeneic Hematopoietic
Stem Cell Transplantation in Myelofibrosis : A Retrospective Study by the Chronic Malignancies Working Party of
the European Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant 25 : 2167-2171, 201911） Murata M, Nishida T, Taniguchi S, et al : Allogeneic transplantation for primary myelofibrosis with BM, peripheral
blood or umbilical cord blood : an analysis of the JSHCT. Bone Marrow Transplant 49 : 355-360, 201412） Deeg HJ, Bredeson C, Farnia S, et al : Hematopoietic Cell Transplantation as Curative Therapy for Patients with
Myelofibrosis : Long-Term Success in all Age Groups. Biol Blood Marrow Transplant 21 : 1883-1887, 201513） Martino R, Altés A, Muñiz-Díaz E, et al : Reduced transfusion requirements in a splenectomized patient undergoingbone marrow transplantation. Acta Haematologica 92 : 167-168, 1994
14） Cervantes F, Dupriez B, Pereira A, et al : New prognostic scoring system for primary myelofibrosis based on a
study of the International Working Group for Myelofibrosis Research and Treatment. Blood 113 : 2895-2901, 200915） Chiusolo P, Bregante S, Giammarco S, et al : Full donor chimerism after allogeneic hematopoietic stem cells transplant
for myelofibrosis : The role of the conditioning regimen. Am J Hematol 96 : 234-240, 2021
16） Bregante S, Dominietto A, Ghiso A, et al : Improved Outcome of Alternative Donor Transplantations in Patients with
Myelofibrosis : From Unrelated to Haploidentical Family Donors. Biol Blood Marrow Transplant 22 : 324-329, 201617） Memoli M, Paviglianiti A, Malard F, et al : Thiotepa-busulfan-fludarabine as a conditioning regimen for patients withmyelofibrosis undergoing allogeneic hematopoietic transplantation : a single center experience. Leuk Lymphoma
62 : 419-427, 2021
18） Yamamoto H, Uchida N, Matsuno N, et al : I.v. BU/fludarabine plus melphalan or TBI in unrelated cord bloodtransplantation for high-risk hematological diseases. Bone Marrow Transplant 50 : 607-609, 201519） Yamamoto H, Uchida N, Yuasa M, et al : A Novel Reduced-Toxicity Myeloablative Conditioning Regimen Using
Full-Dose Busulfan, Fludarabine, and Melphalan for Single Cord Blood Transplantation Provides Durable Engraftment
and Remission in Nonremission Myeloid Malignancies. Biol Blood Marrow Transplant 22 : 1844-1850, 201620） Ueda T, Jo T, Okada K, et al : Curative potential of fludarabine, melphalan, and non-myeloablative dosage of busulfan
in elderly patients with myeloid malignancy. Int J Hematol 111 : 247-255, 2020
21） Ueda T, Maeda T, Kusakabe S, et al : Addition of melphalan to fludarabine/busulfan (FLU/BU4/MEL) provides
survival benefit for patients with myeloid malignancy following allogeneic bone-marrow transplantation/peripheral
blood stem-cell transplantation. Int J Hematol 109 : 197-205, 201922） Takagi S, Ota Y, Uchida N, et al : Successful engraftment after reduced-intensity umbilical cord blood transplantation
for myelofibrosis. Blood 116 : 649-652, 201023） Passamonti F, Cervantes F, Vannucchi AM, et al : Dynamic International Prognostic Scoring System (DIPSS) predicts
No. 6, 2023

401

Asai・Matsuzawa・Kawakami et al.
progression to acute myeloid leukemia in primary myelofibrosis. Blood 116 : 2857-2858, 201024） Gangat N, Caramazza D, Vaidya R, et al : DIPSS plus : a refined Dynamic International Prognostic Scoring Systemfor primary myelofibrosis that incorporates prognostic information from karyotype, platelet count, and transfusion
status. J Clin Oncol 29 : 392-397, 201125） Passamonti F, Giorgino T, Mora B, et al : A clinical-molecular prognostic model to predict survival in patients withpost polycythemia vera and post essential thrombocythemia myelofibrosis. Leukemia 31 : 2726-2731, 201726） Kucybala I, Ciuk S, Teczar J : Spleen enlargement assessment using computed tomography : which coefficientcorrelates the strongest with the real volume of the spleen? Abdom Radiol (NY) 43 : 2455-2461, 201827） Matsuda K, Yamauchi K, Tozuka M, et al : Monitoring of hematopoietic chimerism by short tandem repeats, and theeffect of CD selection on its sensitivity. Clin Chem 50 : 2411-2414, 2004
28） Kharfan-Dabaja MA, Kumar A, Ayala E, et al : Standardizing Definitions of Hematopoietic Recovery, Graft Rejection,
Graft Failure, Poor Graft Function, and Donor Chimerism in Allogeneic Hematopoietic Cell Transplantation : A
Report on Behalf of the American Society for Transplantation and Cellular Therapy. Transplant Cell Ther 27 : 642649, 2021
29） Kanda Y : Investigation of the freely available easy-to-use software ’EZR’ for medical statistics. Bone Marrow
Transplant 48 : 452-458, 201330） Hussein K, Stucki-Koch A, Alchalby H, Triviai I, Kroger N, Kreipe H : Cytokine Expression Pattern in Bone Marrow
Microenvironment after Allogeneic Stem Cell Transplantation in Primary Myelofibrosis. Biol Blood Marrow Transplant
22 : 644-650, 201631） Bognàr T, Bartelink IH, Egberts TCG, et al : Association Between the Magnitude of Intravenous Busulfan Exposure
and Development of Hepatic Veno-Occlusive Disease in Children and Young Adults Undergoing Myeloablative
Allogeneic Hematopoietic Cell Transplantation. Transplant Cell Ther 28 : 196-202, 2022
32） Strouse C, Zhang Y, Zhang MJ, et al : Risk Score for the Development of Veno-Occlusive Disease after Allogeneic
Hematopoietic Cell Transplant. Biol Blood Marrow Transplant 24 : 2072-2080, 201833） Shouval R, Vega Y, Fein JA, et al : Allogeneic hematopoietic stem cell transplantation with fludarabine, busulfan, andthiotepa conditioning is associated with favorable outcomes in myelofibrosis. Bone Marrow Transplant 55 : 147-156,
2020（2023. 5. 12 received ; 2023. 8. 21 accepted）

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