New Conditioning Regime For RRMS

Intermediate-Intensity Chemotherapy (IDCT)

The standard of treatment for patients with highly aggressive Relapse-Remitting Multiple Sclerosis (RRMS)

Intermediate Intensity Chemotherapy (IDCT) + AHSCT

Intermediate-intensity chemotherapy followed by autologous transplantation of hematopoietic stem cells (AHSCT) is the standard of treatment for the part of patients with highly aggressive relapse-remitting multiple sclerosis (RRMS).

There are several most used conditioning regimens, previous EBMT recommendations recommended the use of "intermediate intensity" regimen namely cyclophosphamide 200 mg/kg with T-cell depleting.

However, there are currently no data on the conduct of randomized studies that would compare the effectiveness and toxicity of different regimens.

Aims

Comparison of the toxicity of the following conditioning regimens
1st Regime: Cyclophosphamide + Rituximab (Cph+R)
2nd Regime: Fludarabine + Cyclophosphamide + Rituximab (Flu/Cph+R)
as a conditioning regimen before AHSCT for the treatment of Multiple Sclerosis

Methods:

In active study with retrospective control included 94 patients with Multiple Sclerosis
Median age 43 years (64 men and 30 women)

RRMS — 31 patients
PPMS — 39 patients
SPMS — 24 patients

EDSS score was 1.5 — 7.5 (average 4.5).

All patients received HDCT and ASCT in NMSC named after N.I. Pirogov (2018 - 2021)

Conditioning regimens:

1

Cph+R (49 patients)

Cyclophosphamide 200 mg/kg - 4 days
+
Rituximab 500 mg/m2 - 1 day
2

Flu/Cph+R (45 - patients)

Fludarabine 150mg/m2 - 6 days
+
Cyclophosphamide 100 mg/kg - 2 days
+
Rituximab 500 mg/m - 1 day

Results:

Hematologic toxicity of different regimens: "Cph+R" and "Flu/Cph+R"

Duration of neutropenia was— 7-12 days (average 9.6) in Cph+R group and 3-10 (average 6.3) in Flu/Cph+R group

Duration of thrombocytopenia in Cph+R regimen — 7.7 days, Flu/Cph+R -3.4 days

There are 31 (63%) patients received platelet transfusion in Cph+R group and 6 (12%) patients in Flu/Cph+R group. Anemia Grade II (CTCAE 5.0, 2017) was identified in booth regimens

Anemi grade III was most commonly appear in Flu/Cph+R regime (n=4 — 8%)

Range of immunosuppression

The minimal count of lymphocytes was significant lower in Flu/Cph+R group 0,0001 - 0,1 X1O9/1 (average 0.008X109/!), than in Cph+R group witch minimal count of lymphocyte was (0,001 — 0,1 xl09/l (average 0.03xl09/l) (p<0.05)
Non-hematologic toxicity

Oral mucositis (WHO criteria) was observed at 13 (26%) patients Cph+R group (Grade I - 61,5 %; Grade II - 38,5 %) in Flu/Cph+R 4 (9%) patients (Grade I - 100 %)
Enteropathy

Enteropathy more common at Cph+R group - 16 % (n=8), Grade I -10%, Grade II — 4%, Grade III — 2%, in Flu/Cph+R — 2 (4%) patients had enteropathy (Grade II)
Cardiotoxic

Cardiotoxic effects was observed once at Cph+R group (atrial fibrilation), no cases in Flu/Cph+R group
Hepatic toxicity

Hepatic toxicity (CTCAE 5.0, 2017) was observed at 9 (18%) patients Cph+R group (Grade I - 10%; Grade II - 8%) in Flu/Cph+R 9 (20%) patients (Grade 1-15 %, Grade II — 5%).
Infection

Infection in Cph+R group 13 (26%) patients had infection complications (7 local infections, 6 blood stream infections), in Flu/Cph+R — 5 (10%) patients had infection complications complications -1 local infection, 1 catheter — related infection, 3 neutropenic fever).
There are no cases of transplant-related mortality in booth regimes.

Summary/Conclusion:

The effectiveness of the IDCT method in the treatment of aggressive forms of MS has been proven, at the same time, this method has significant limitations due to high toxicity.

Our regime (Flu/Cph+R) showed a significantly deeper lymphodepletion, with less toxicity and a reduced incidence of infectious complications.

Thus, this method can be applied to the larger number of patients.

National Medical Surgical Center named after Pirogov N.I.

Denis Fedorenko

Hematologist, Professor
Doctor of Medical Sciences
Vladimir Melnichenko

Head of the Department
Doctor of Medical Sciences
Anatoly Rukavitsyn

Hematologist, Oncologist
Candidate of Medical Sciences

"New Lymphoablative Conditioning Regime For Multiple Sclerosis - First Results From Russian Pilot Study"
Article authors: Denis Fedorenko, Vladimir Melnichenko, Anatoly Rukavitsyn. FBGU "National Medical Surgical Center named after Pirogov N.I." Ministry of Health Russian Federation,

Abstract Book Citations: Authors, Title, HemaSphere, 2022;6:(S3):pages. The individual abstract DOIs can be found at
https://journals.lww.com/hemasphere/pages/default.aspx.

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The authors are responsible for all content in their abstracts including accuracy of the facts, statements, citing resources, etc.