Correspondence

Global Health & Medicine. 2024; 6(4):277-281.
DOI: 10.35772/ghm.2024.01021

Prospective therapeutic studies of disseminated extranodal large
B-cell lymphoma including intravascular large B-cell lymphoma
Tomoyuki Sakai1,*, Yusuke Ueda1, Hiroto Yanagisawa1, Kotaro Arita1, Haruka Iwao1, Kazunori Yamada1,2, Shuichi Mizuta1,
Hiroshi Kawabata1,3, Toshihiro Fukushima1, Katsunori Tai4, Shinji Kishi4, Koji Morinaga5, Jun Murakami6,
Hiroyuki Takamatsu7,8, Yasushi Terasaki9, Nobuyuki Yoshio10, Yukio Kondo11, Hirokazu Okumura11, Sadaya Matano12,
Masaki Yamaguchi13, Hiroshi Tsutani14, Yasufumi Masaki1
1

Department of Hematology and Immunology, Kanazawa Medical University, Ishikawa, Japan;
Department of Medical Education, Kanazawa Medical University, Ishikawa, Japan;
3
Department of Hematology, National Hospital Organization Kyoto Medical Center, Kyoto, Japan;
4
Department of Hematology and Oncology, University of Fukui Hospital, Fukui, Japan;
5
Department of Hematology and Oncology, Fukui Prefectural Hospital, Fukui, Japan;
6
Clinical Laboratory, Transfusion Medicine and Cell therapy, Toyama University Hospital, Toyama, Japan;
7
Department of Hematology, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Ishikawa, Japan;
8Department of Internal Medicine, Keiju Kanazawa Hospital, Ishikawa, Japan;
9
Division of Hematology, Toyama City Hospital, Toyama, Japan;
10
National Hospital Organization Kanazawa Medical Center, Ishikawa, Japan;
11
Toyama Prefectural Central Hospital, Toyama, Japan;
12
Tonami General Hospital, Toyama, Japan;
13
Ishikawa Prefectural Central Hospital, Ishikawa, Japan;
14
Department of Hematology and Oncology, National Hospital Organization Awara Hospital, Fukui, Japan.
2

Abstract: This study aimed to establish a standard treatment for disseminated extranodal large B-cell lymphoma,
including intravascular large B-cell lymphoma (DEN-LBCL/IVL), and to validate the clinical diagnostic criteria we
proposed. Between 2006 and 2016, 22 patients were enrolled in a clinical trial conducted by the Hokuriku Hematology
Oncology Study Group. The first cycle of chemotherapy consisted of dose-reduced cyclophosphamide, doxorubicin,
vincristine, and prednisolone (CHOP) with delayed administration of rituximab. From the second to the sixth cycle,
patients received conventional rituximab and CHOP therapy. The primary endpoint was overall survival (OS), while thesecondary endpoints included the complete response (CR) rate and time to treatment failure (TTF). The results showed
a CR rate of 73%, a median OS of 65 months, and a median TTF of 45 months. These findings indicate that patientswith DEN-LBCL/IVL were effectively treated with our new chemoimmunotherapy regimen. Our clinical diagnostic
criteria are useful for identifying patients who require early intervention.
Keywords: intravascular large B-cell lymphoma, random skin biopsy, R-CHOP, clinical diagnostic criteria

Introduction
Intravascular large B-cell lymphoma (IVL) was first
documented by Pfleger and Tappeiner in 1959 (1).
IVL is defined as a subtype of diffuse large B-cell
lymphoma (DLBCL) and recognized in the 2017 WHOclassification (2). An Asian variant characterized byhemophagocytic syndrome was established by Murase
et al. (3). Most IVL studies involve small, retrospective
case analyses. A large-scale prospective study is needed
to evaluate treatment protocols. IVL diagnosis is limited
to cases with confirmed occlusion of vascular lumensby neoplastic B-cells. However, some cases with diffuse
large lymphoid cell proliferation in the bone marrow(BM) without clear masses might still originate from
IVL. These include primary BM DLBCL or disseminatedextranodal DLBCL (DEN-LBCL) without masses.
Patients with pathologically confirmed IVL and thosewith clinically suspected IVL would experience similar
rapidly deteriorating clinical courses, which could lead todeath. Recently, Suzuki et al. (4) reported no significant
differences in characteristics and prognosis between IVL
expressing PD-L1 and extranodal lymphomas. Early
clinical diagnostic criteria for DEN-LBCL/IVL havebeen reported to be useful for diagnosis (5), and randomskin biopsy (RSB) and BM biopsies are recommended(6). Most IVL patients present with multiple organ
involvement and are classified as Stage IV according(277)

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to the Ann Arbor classification. They also have highrisk scores on the International Prognostic Index (IPI)(7). Standard treatment for DLBCL, such as CHOP
chemotherapy (8), is considered for IVL. Anthracyclinebased chemotherapy has shown effectiveness (9).
Murase et al. (10) reported that patients treated with nonanthracycline-based chemotherapy had a poor prognosis.
Rituximab-containing chemotherapy significantly
improved outcomes in Japanese patients (11). To reduce
the risk of infusion reactions, rituximab should be
administered after debulking with CHOP. For patients
expected to have severe bone marrow suppression due to
BM infiltration, a reduced CHOP dose is recommended
initially. We developed a new protocol with reduced-dose
CHOP followed by rituximab and evaluated its efficacy.
Additionally, we assessed early clinical diagnostic
criteria and pathological diagnostic rates, and reportthese findings.
Study methods and analysis
In this study, patients aged 20 years or older with primary
DEN-LBCL/IVL were enrolled, confirmed pathologicallyor meeting clinical diagnostic criteria (Supplemental
Table S1, https://www.globalhealthmedicine.com/site/
supplementaldata.html?ID=85). Rapidly progressive
cases began treatment based on clinical diagnosis.
Exclusion criteria included suspected connective tissue
disease/vasculitis, severe infections, prior chemotherapy,
human immunodeficiency virus (HIV), human T-cellleukemia virus type 1 (HTLV-1), and hepatitis B
virus (HBV) antigen positivity, among others. Written
informed consent was obtained, the trial was approvedby institutional review boards, registered in the UMIN
Clinical Trials Registry (ID: 000001309), and conductedin accordance with the Declaration of Helsinki.
The first chemotherapy cycle involved two-thirds ofthe conventional dose of each CHOP drug, except for
prednisolone. Rituximab was administered on day 7 if
CD20 expression was confirmed. Dosage adjustments
were permitted for patients with BM suppression, poor
performance status (PS), or advanced age. From thesecond to sixth cycles, conventional R-CHOP therapy
was given. Criteria for continuing to the second cycle
included fever reduction, PS improvement, LDH
normalization, and neutrophil count recovery. Treatment
was discontinued if criteria were not met by day 28.
After six R-CHOP cycles, peripheral blood stem cell
(PBSC) harvesting was performed for younger patients(< 70 years) or those with improved PS. High-dose
chemotherapy with autologous PBSC transplantation(autoPBSCT) followed PBSC harvesting. In older
patients (≥ 70 years) or those with poor PS, additional
chemotherapy with high-dose methotrexate (MTX) andrituximab was administered to prevent central nervous
system (CNS) recurrence and improve prognosis.
The protocols for PBSC harvesting and high-dose

chemotherapy combined with autoPBSCT were notspecified in this study. Preventative measures included
sulfamethoxazole/trimethoprim to prevent Pneumocystis
infection and additional antifungal agents. Patients
positive for hepatitis B core or surface antibodies weremonitored monthly for HBV-DNA and treated withantiviral agents if needed.
IVL rarely forms masses, so we created our own
response evaluation criteria (Supplemental Table
S2, https://www.globalhealthmedicine.com/site/
supplementaldata.html?ID=85). The primary endpoint
was overall survival (OS), with secondary endpoints
including complete remission (CR) rate, concordance
rate between clinical diagnosis and pathologicallyconfirmed diagnosis in clinically diagnosed patients,
diagnostic yields of BM and RSB, and time to treatment
failure (TTF). TTF was the interval from enrollment todisease progression or death. OS and TTF were analyzed
using the Kaplan-Meier method.
Clinical trial outcomes and diagnostic evaluations
Patient characteristics
A total of 22 patients were recruited from six medical
institutions between March 2006 and March 2016.
There were 12 men and 10 women, with a medianage of 74 years (range 52–89 years) (Supplemental
Table S3, https://www.globalhealthmedicine.com/site/
supplementaldata.html?ID=85). The median follow-up
for survivors was 35 months.
Survival and treatment outcomesSix patients (38%) experienced recurrence, two ofwhom received salvage treatment and survived (117
and 124 months). Eleven patients died; five died during
treatment before CR confirmation. Causes of death
included pneumonia (n = 1), sepsis (n = 1), multiple
organ failure (n = 2), and disease progression (n = 1).
Four died after recurrence, and two in remission fromcomplications. Median OS and TTF were 65 and 46
months, respectively (Figure 1A.1B).
Of 22 patients, 16 (73%) achieved CR/ CR
unconfirmed (CRu), three had progressive Disease (PD),and three were not Evaluable (NE) (Table 1). The first
patient died of organ failure after the first chemotherapy
cycle, the second of pneumonia after the third cycle, andthe last was removed after the first cycle due to bronchialpneumonia.
Diagnostic accuracy and effectivenessTen patients started treatment based on clinicalcriteria alone; eight were later confirmed with IVL bypathological examination, giving an 80% concordance
rate. The remaining two were diagnosed with DEN-

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Figure 1. (A) Overall survival. The median overall survival(OS) was 65 months (11 deaths). Of these, five died during
treatment without achieving complete response (CR). The
causes of death included pneumonia (1), sepsis (1), multiple
organ failure (2), and disease progression (1). Four patientsdied after recurrence, and two died while in remission ofcomplications (one from cerebral infarction and the other frompneumonia). (B) Time to treatment failure. The median timeto treatment failure (TTF) was 46 months, with six patients
having recurrence. Of these, two patients received salvage
treatment and were alive at the time of the last follow-up.
Table 1. Response

CR/CruPD
NE
RelapseAlln = 22

R-CHOPn = 15

PBSCT+
n=4

MTX+
n=3

16
3
3
6

9
3
3
4

4
1

3
1

R-CHOP: R-CHOP therapy only. PBSCT+: Six cycles of R-CHOP,
followed by PBSCT. MTX+: Six cycles of R-CHOP, followed by twocycles of high-dose MTX (2 g/m2 as a single dose) and R-CHOP. CR:
complete response, CRu: unconfirmed, PD: progressive disease, NE:
not evaluable.

LBCL/IVL by BM smears, with monoclonal B-cell
populations detected by flow cytometry.
BM examination diagnosed 14 (64%) of 22 patientswith DEN-LBCL/IVL. RSB biopsy confirmed six (35%)
of 17 patients. Three patients showed no lymphoma
cells in BM or skin (Supplemental Table S3, https://www.globalhealthmedicine.com/site/supplementaldata.
html?ID=85).
Discussion
Most studies on IVL have examined a limited numberof cases, often retrospectively, focusing on preexisting

patient data. The standard treatment for IVL remains
unestablished, with R-CHOP chemotherapy being themost administered regimen. A Japanese retrospective
study (11) on 49 IVL patients treated with rituximabcontaining chemotherapy reported an 82% CR rate, with
progression-free survival (PFS) and OS rates at 2 yearsof 56% and 66%, respectively, aligning with outcomes inhigh-risk DLBCL patients classified by the IPI. In North
America, a study (12) of 29 IVL patients revealed that 18
underwent first-line chemotherapy, with 15 completingit. Of those, 53% achieved CR, and the overall threeyear survival rate was 42.7%, with a 64.2% event-freesurvival rate. In a retrospective study (13) of 12 patientswith IVL conducted in China, 11 received R-CHOP
therapy, and the overall response rate (ORR) and CR rate
were 90.1% and 66.7%, respectively.
In the present study, the CR/CRu rate was 73%,
with median OS and TTF of 65 and 46 months,
respectively. To mitigate infusion reactions and severe
BM suppression during the first chemotherapy cycle, a
new regimen of dose-reduced CHOP (two-thirds of thenormal dose) with delayed rituximab administration wasused. The CR rate, OS, and TTF achieved were similar
to those reported in previous studies (Supplemental
Table S4, https://www.globalhealthmedicine.com/site/
supplementaldata.html?ID=85). Evaluations of highdose chemotherapy combined with autoPBSCT in
IVL patients are also limited to retrospective analyses.
Meissner et al. (14) conducted a study on 11 IVL patientsregistered in the European Society for Blood and Marrow
Transplantation database, treated with autoPBSCT. They
reported two-year PFS and OS rates of 81% and 91%,
respectively. Similarly, Kato et al. (16) retrospectively
analyzed 61 IVL patients treated with autoPBSCT,
reporting three-year OS and PFS rates of 89.1% and82.8%, respectively.
In our study, four patients underwent high-dose
chemotherapy with autoPBSCT. One patient experienced
recurrence, but the others remained alive without
recurrence at the time of analysis, with TTFs of 35,
43, 112, and 119 months, respectively. Three elderly
patients ineligible for autoPBSCT received additional
chemotherapy, including high-dose MTX. One hada recurrence in the BM, one died in remission from
cerebral infarction, and the third was alive without
recurrence at analysis.
Next, we assessed the concordance rate between
clinical and pathological diagnoses in patientsdiagnosed using clinical criteria alone (Supplemental
Table S1, https://www.globalhealthmedicine.com/site/
supplementaldata.html?ID=85). Of the 22 patients inthe clinical trial, 10 started treatment based solely onthese criteria. Eight were later definitively diagnosed
with IVL via pathological examination, resulting in an
80% diagnostic concordance rate, which is satisfactorily
high. Given the rapid progression of DEN-LBCL/IVL,
patients often become too advanced for successful(279)

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treatment while awaiting a pathological diagnosis. The
clinical diagnostic criteria used in this study are thus
highly beneficial but do not always ensure an accurate
diagnosis. Close monitoring and assessment are crucial
when initiating treatment without a pathologicaldiagnosis. Patients should be well-informed about
their diagnosis and treatment. Ideally, treatment shouldcommence after a definitive pathological diagnosis.
The diagnostic yields of BM examination and
RSB were also evaluated. BM examination identified
14 patients with DEN-LBCL/IVL (64%). RSB were
performed on 17 patients, detecting IVL in six (35%).
Only three patients showed no infiltration in the BM or
skin. Two of these were definitively diagnosed with IVL
in other organs (spleen and brain). The last patient only
had a clinical diagnosis of DEN-LBCL/IVL. RSB shouldbe performed on all eligible patients as it is minimallyinvasive. Matsue et al. (6) reported a 71% positivity
rate in RSB. In a study conducted by Maekawa et al.
(17) in nine patients with IVL, they found significant
detection rates of tumor cells in various skin layers,
suggesting random skin biopsy using a 4-mm punchis effective for patients with thrombocytopenia andcoagulation abnormalities. In the present study, only twopatients were diagnosed with IVL by skin biopsy alone.
However, because this procedure is minimally invasive,
it should be performed on all eligible patients.
Shimada et al. (18) conducted a multicenter,
prospective study on a chemoimmunotherapy regimenof R-CHOP followed by rituximab with high-dose
MTX and additional R-CHOP cycles. The study showed
this regimen's effectiveness in treating IVL patients.
However, the included cases had relatively favorable
conditions, with better PS and organ function. In
practice, many IVL cases are severe and life-threatening;
thus, after rapid BM and skin biopsy examination,
chemotherapy may need to start before a definitive
pathological diagnosis if the patient's PS deteriorates.
Respecting Shimada's data, we conducted this trial for
more severe cases. Early treatment based on clinicaldiagnostic criteria could save many DEN-LBCL/IVL
patients, especially those of advanced age or withmultiple organ failure.
Our study had several limitations. First, the caseenrollment period was very long, spanning 10 years,
with only 22 patients registered, averaging just 2.2 cases
per year. Second, due to the long enrollment period, theobservation period varied greatly according to the dateof registration; however, the survival curves did notreach the plateau phase in both OS and TTF.
In conclusion, patients with DEN-LBCL,
including IVL, were effectively treated with a new
chemoimmunotherapy regimen starting with dosereduced CHOP and delayed rituximab, followed byconventional R-CHOP. The clinical diagnostic criteria
were helpful for early intervention. Larger studies areneeded to confirm these findings.

Acknowledgements
We thank all the staff in Hokuriku Hematology Oncology
Study Group who participated in the study.
Funding: None.
Conflict of Interest: YM received research grants from
Kyowa Kirin Pharma, Astellas Pharma, Eisai Pharma,
Asahi Kasei Pharma, Daiichi-Sankyo Pharma, Taisho
Pharma, Takeda Pharma, Chugai Pharma, Teijin Pharma,and Japan Blood Product Organization outside thesubmitted work. The other authors have no conflicts ofinterest to declare.
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---Received March 2, 2024; Revised July 8, 2024; Accepted July30, 2024.
Released online in J-STAGE as advance publication August 3,
2024.
*Address correspondence to:
Tomoyuki Sakai, Department of Hematology and Immunology,
Kanazawa Medical University, 1-1 Daigaku, Uchinada-machi,
Kahoku-gun Ishikawa 920-0293, Japan.
E-mail: pochi@kanazawa-med.ac.jp(281)