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Cyclophosphamide (Cytoxan) In MS

    Abstracts

  1. High-Dose Cyclophosphamide for Moderate to Severe Refractory Multiple Sclerosis
    2006 Oct;63(10):1388-93

  1. Pulse Cyclophosphamide Plus MethylPrednisolone Induces Myelin-Antigen-specific IL-4-secreting T-Cells In MS
    Clin Immunol ImmunoPathol 1998 Jul;88(1):28-34

  2. The Immune Profile of Multiple Sclerosis: T-Lymphocyte Effects Predominate All Other Factors in Cyclophosphamide Treatments
    J NeuroImmunol 1995 Dec 31;63(2):133-42

  3. Elevated Interleukin-12 in Progressive Multiple Sclerosis Correlates With Disease Activity & Is Normalized by Pulse Cyclophosphamide Therapy
    J Clin Invest 1998 Aug 15, 102:4, 671-8

  4. Bladder Cancer In Patients With Multiple Sclerosis Treated With Cyclophosphamide
    J Urol 1998 Jun, 159:6, 1881-4

  5. Immune deviation Following Pulse Cyclophosphamide/MethylPrednisolone Treatment of Multiple Sclerosis: Increased Interleukin-4 Production & Associated Eosinophilia
    Ann Neurol 1997 Sep, 42:3, 313-8

  6. Side-Effects of IV Cyclophosphamide Pulse Therapy
    Lupus, 1997, 6:3, 254-7

  7. Multiple Spontaneous IntraCerebral Hemorrhages in Progressive Systemic Sclerosis
    Rev Rhum Engl Ed, 1998 Jun, 65:6, 437-40

  8. Stabilization of rapidly worsening Multiple Sclerosis for 36 months in patients treated with Interferon-ß plus Cyclophosphamide followed by Interferon-ß
    J Neurol 2004 Dec;251(12):1502-6

  9. Multiple Sclerosis: long-term remission after a high dose of Cyclophosphamide
    Acta Neurol Scand 2005 Mar;111(3):195-8

  10. Cyclophosphamide is effective in stabilizing rapidly deteriorating Secondary/Progressive Multiple Sclerosis
    J Neurol 2003 Jul;250(7):834-8

  11. Treatment of Progressive forms of Multiple Sclerosis by Cyclophosphamide: a cohort study of 490 patients
    J Neurol Sci 2004 Mar 15;218(1-2):73-7

  12. Treatment of Progressive Multiple Sclerosis with monthly pulsed Cyclophosphamide-MethylPrednisolone: predictive factors of treatment response
    Rev Neurol (Paris) 2004 Jul;160(6-7):659-65



      Additional Abstracts

          WWW Links

  1. Reduction of Disease Activity and Disability With High-Dose Cyclophosphamide in Patients With Aggressive Multiple Sclerosis
    by: Krishnan C, Kaplin AI, Brodsky RA, Drachman DB, Jones RJ, Pham DL, Richert ND, Pardo CA, Yousem DM, Hammond E, Quigg M, Trecker C, McArthur JC, Nath A, Greenberg BM, Calabresi PA, Kerr DA
    Arch Neurol 2008 Aug;65(8):1044-51


  2. Revimmune for Autoimmune Disease
    by: Accentia BioPharmaceuticals

  3. Accentia Biopharmaceuticals Files for Phase III Revimmune Trial
    by: FDA News

  4. Revimmune Uses An Approved Drug In A New Patent-Pending Method To Eliminate Autoimmunity
    by: Medical News Today
    March 3, 2007




#1

Pulse Cyclophosphamide Plus MethylPrednisolone Induces Myelin-Antigen-specific IL-4-Secreting T-Cells In Multiple Sclerosis

Takashima H, Smith DR, Fukaura H, Khoury SJ, Hafler DA, Weiner HL
Clin Immunol ImmunoPathol 1998 Jul;88(1):28-34
Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, Massachusetts, 02115, USA
UI# 98350092
Abstract

Multiple Sclerosis (MS) is a presumed Cell-Mediated Th1-type AutoImmune Disease.

Thus therapies which decrease T-Cells secreting IFN-gamma production or increase IL-4 production would be expected to have an ameliorating effect on MS.

We have previously reported increased Anti-CD3-induced IL-4 secretion by T-Cells in Progressive MS patients treated with Cyclophosphamide plus MethylPrednisolone (CY/MP) which was associated with Eosinophilia.

To investigate whether the increased IL-4 secretion was Myelin Antigen specific, we generated 3990 short-term T-Cell lines to Myelin Basic Protein (MBP), ProteoLipid Protein (PLP), or Tetanus Toxoid (TT) from 31 Progressive MS patients:

  • 11 MS patients treated with CY/MP
  • 10 MS patients treated with MP alone
  • 10 untreated MS patients.

We found increased frequencies of both MBP- and PLP-specific IL-4-secreting T-Cell lines in CY/MP-treated patients compared to untreated MS patients.

However, no change in the frequency of TT-specific IL-4-secreting T-Cells was observed. MP treatment alone did not increase the frequency of Antigen-specific IL-4-secreting T-Cell lines.

These results demonstrate Immune deviation favoring Th2-type responses specific to AutoAntigens following pulse Cyclophosphamide therapy in MS patients.

Copyright 1998 Academic Press.


#2

The Immune Profile Of Multiple Sclerosis:
T-Lymphocyte Effects Predominate All Other Factors In Cyclophosphamide Treatments

Strauss K, Hulstaert F, Deneys V, Mazzon AM, Hannet I, De Bruyere M, Reichert T, Sindic CJ
J NeuroImmunol 1995 Dec 31;63(2):133-42
Becton Dickinson ImmunoCytometry Systems, Erembodegem-Aalst, Belgium
UI# 96133572
Abstract

It is widely believed that Multiple Sclerosis is a T-Cell mediated AutoImmune Disease associated with abnormalities in ImmunoRegulation.

This large, prospective study evaluated the Lymphocyte Immunophenotypic profile of 246 MS patients, divided clinically into a Relapsing/Remitting group (n = 176) and a Progressive group (n = 70), and compared their results to those of 117 healthy controls.

All patients were found to have significantly elevated percentage and absolute numbers of IL2R+CD3+ cells as well as depressed percentages of CD45RA+CD4+ cells.

However, when the factor of treatment with Cyclophosphamide (CY) versus no treatment or treatment with other agents was used to group patients, dramatic declines in both percentages and absolute numbers of CD45RA+CD4+ cells were discovered.

These declines were associated specifically with CY and and could be explained by this factor independent of the clinical state of the patient. The effects were seen in patients undergoing current treatment or in those exposed to CY in the near or remote past.

These findings highlight the confounding effect of specific treatments on the Immune profile of MS patients groups and suggest that there may be important implications for cellular function and clinical outcome in these and other patient groups.



#3

Elevated InterLeukin-12 in Progressive Multiple Sclerosis Correlates With Disease Activity & Is Normalized by Pulse Cyclophosphamide Therapy

Comabella M; Balashov K; Issazadeh S; Smith D; Weiner HL; Khoury SJ
J Clin Invest 1998 Aug 15, 102:4, 671-8

Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA

UI# 98376474
Abstract

Multiple Sclerosis is postulated to be a Th1-type Cell-Mediated AutoImmune Disease. We investigated Cytokine profiles in patients with Progressive Multiple Sclerosis by using intracytoplasmic staining.

We found increased IL-12 production by Monocytes and increased IFN-gamma production by T-Cells in untreated patients as compared with controls.

In patients treated with Methotrexate, MethylPrednisolone, or Cyclophosphamide/MethylPrednisolone (CY/MP), only CY/MP treatment normalized the elevated IL-12 production.

Furthermore, CY/MP-treated patients had decreased IFN-gamma and increased IL-4, IL-5, and TGF-ß expression.

Patients followed prospectively before and after starting CY/MP treatment showed a gradual decrease in IL-12 and IFN-gamma production and an increase in IL-4 and IL-5.

In vitro, addition of 4-HydroperoxyCyclophosphamide, a metabolite of Cyclophosphamide decreased IL-12 production in MonoNuclear Cell cultures.

When patients were classified as having active or stable disease, IL-12 production correlated with disease activity.

In summary, our results demonstrate a Th1-type Cytokine bias in Peripheral Blood MonoNuclear Cells of untreated Progressive MS patients that is reversed by CY/MP treatment and is associated with Th2 and TGF-ß (Th3) type responses.

These findings provide a basis for Immune monitoring of patients with MS and suggest that treatments that downregulate IL-12 may prove to be beneficial in Progressive MS.



#4

Bladder Cancer In Patients With Multiple Sclerosis Treated With Cyclophosphamide

De Ridder D; van Poppel H; Demonty L; DHooghe B; Gonsette R; Carton H; Baert L
J Urol 1998 Jun, 159:6, 1881-4
Catholic UnivLeuven, Dept of Urology, UZ Gasthuisberg, Belgium
UI# 98258427
Abstract

Purpose
We define the risk of Bladder Cancer in Multiple Sclerosis related to the use of Indwelling Catheters and Cyclophosphamide administered as an ImmunoModulating agent.

Materials & Methods
We retrospectively reviewed the records of 2,351 patients with Multiple Sclerosis referred to the National Center for Multiple Sclerosis.

Results
Of the 2,351 patients 2 women and 5 men (0.29%) had Bladder Cancer. Of the 850 chronically catheterized patients the incidence was 0.7%.

One patient with Cancer performed intermittent catheterization for a rate of 0.23% in this group.

In a subgroup of 70 patients treated with Cyclophosphamide 5 chronically catheterized patients (5.7%) had Bladder Cancer.

Hematuria was the most common presenting symptom. These data were compared with those in the literature on Bladder Cancer in Spinal Cord injury.

Conclusions
These data suggest a possible synergistic role of Cyclophosphamide and chronic catheterization in the induction of secondary Bladder Cancer.

Regular Cystoscopy is warranted in these patients to allow early detection of Bladder Tumors. Nitric Oxide metabolism may be an important factor in the Carcinogenesis of this type of Bladder Cancer.



#5

Immune deviation Following Pulse Cyclophosphamide/MethylPrednisolone Treatment of Multiple Sclerosis: Increased InterLeukin-4 Production & Associated Eosinophilia

Smith DR; Balashov KE; Hafler DA; Khoury SJ; Weiner HL
Ann Neurol 1997 Sep, 42:3, 313-8
Harvard Medical School, Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA 02115, USA
UI# 97450811
Abstract

Multiple Sclerosis (MS) is postulated to be a Th1-type Cell-mediated AutoImmune Disease.

Thus therapies that decrease T-Cell Interferon-gamma (IFN-gamma) production or increase InterLeukin-4 (IL-4) production would be expected to have an ameliorating effect on MS.

Some Progressive MS patients receiving pulse Cyclophosphamide therapy developed peripheral blood Eosinophilia. We investigated whether Cyclophosphamide treated patients had Immune Deviation toward Th2 responses.

We measured Cytokine production in patients receiving either monthly IntraVenous MethylPrednisolone (MP), IntraVenous Cyclophosphamide plus MethylPrednisolone (CY/MP), Methotrexate, IFN-ß-1b, in untreated MS patients, and in healthy controls.

Minimal IL-4 was secreted in untreated patients (129 +/- 62 pg/ml), Methotrexate treated patients (99 +/- 79 pg/ml), and healthy controls (50 +/- 13 pg/ml). A marked increase in IL-4 was observed in CY/MP patients (1,503 +/- 291 pg/ml).

Patients treated with MP (418 +/- 160 pg/ml) or IFN-ß-1b (425 +/- 167 pg/ml) showed small increases. Eosinophilia in CY/MP-treated patients (6.0 +/- 0.7%) correlated with increased IL-4. IL-10 production was also increased in CY/MP-treated patients.

Both CY/MP- and MP-treated groups had decreased production of IFN-gamma compared with untreated MS.

These findings demonstrate pronounced Immune Deviation favoring Th2-type responses after pulse Cyclophosphamide therapy.



#6

Side-Effects of IV Cyclophosphamide Pulse Therapy

Martin F; Lauwerys B; Lefèbvre C; Devogelaer JP; Houssiau FA
Lupus, 1997, 6:3, 254-7
Saint-Luc Univ Hospital, Louvain Medical School, Rheumatology Dept, Bruxelles, Belgium
UI# 97258258
Abstract

We reviewed the side-effects of IntraVenous (I.V.) Cyclophosphamide (CPM) pulse therapy in a group of 75 patients suffering from various AutoImmune disorders (mostly Systemic Lupus Erythematosus and Vasculitis) who received a total of 451 I.V.

CPM pulses, given on a monthly basis (mean +/- s.d. CPM dose per pulse: 764 +/- 217 mg; mean +/- s.d. follow-up period: 26.7 +/- 22.1 mon).

Infection was the most common side-effect (30 episodes in 21 patients; 28% of the patients) but rarely required in-patient treatment (8 episodes in 7 patients; 9% of the patients).

No relationship could be found between the occurrence of infection and the dose of CPM or of GlucoCorticoids. Other side-effects were rare. Only one patient suffered from Neutropenia.

Haemorrhagic Cystitis was never observed nor did premature Ovarian failure in the 25 female patients at risk.

Four patients developed Neoplasia and three died suddenly a few days after receiving a CPM pulse but the causal relationship between CPM therapy and these poor outcomes is speculative.

Taken together, our data confirm in a large group of patients that I.V. CPM pulse therapy is relatively safe. In particular, the rate of severe infection requiring in-patient treatment is rare (1.8% of 451 pulses.).



#7

Multiple Spontaneous IntraCerebral Hemorrhages in Progressive Systemic Sclerosis

Andonopoulos AP; Maraziotis T; Rigas G; Yarmenitis S; Papapetropoulos T
Rev Rhum Engl Ed 1998 Jun, 65:6, 437-40
Patras Regional Univ Hospital, Division of Rheumatology, Univ of Patras School of Medicine, Greece
UI# 98334993
Abstract

A 64-year-old woman with a two-year history of diffuse Scleroderma responsible for severe Interstitial Lung Disease was admitted for recurrent loss of consciousness.

Her treatment at the time consisted of a CorticoSteroid and monthly Cyclophosphamide pulses.

Computed Tomography and Magnetic Resonance Imaging of the Brain revealed two Hemorrhagic lesions in the Left Frontal and Temporal Lobes, respectively.

Amyloidosis and/or Vasculitis may have contributed to these Lesions.



#8

Stabilization Of Rapidly Worsening Multiple Sclerosis For 36 Months In Patients Treated With Interferon-ß Plus Cyclophosphamide Followed By Interferon-ß

Patti F, Reggio E, Palermo F, Fiorilla T, Politi G, Nicoletti A, Reggio A
J Neurol 2004 Dec;251(12):1502-6
Department of Neurological Sciences, Via Santa Sofia 78, 95123, Catania, Italy
PMID# 15645351
Abstract

Cyclophosphamide (CTX) is an Alkylating agent related to Nitrogen Mustards, whose AntiInflammatory and ImmunoSuppressive effects have been utilized to treat selected cases, of Multiple Sclerosis with a Progressive and worsening course.

To halt the progression of disease, in patients refractory to disease modifying drugs, CTX has been given, and several open-label studies have recently shown clinical benefits.

In a previous study we demonstrated the effectiveness of a combination of IV monthly pulses of CTX and Interferon-beta (IFN-ß), in 10 patients with "rapidly transitional" form of Multiple Sclerosis. Characterized by severe and frequent attacks and rapid progression of disability.

The present study reports the clinical and MRI follow-up, compared to the pre-treatment period, 36 months after the discontinuation of CTX.

    Showing the maintenance of the results obtained in:
    1. Relapse Rate (p < 0.001)
    2. EDSS (p < 0.001)
    3. T2 MRI total lesion load (p < 0.001)
    4. T2 lesions number (p < 0.001)

These encouraging findings and the absence of significant recorded side effects, affirm that the association of CTX plus Interferon-ß is amenable, safe and can be recommended in rapidly worsening MS patients.



#9

Multiple Sclerosis: Long-Term Remission After A High Dose Of Cyclophosphamide

Bittencourt PR, Gomes-da-Silva MM
Acta Neurol Scand 2005 Mar;111(3):195-8
Unidade de Neurologia Clinica, Curitiba, Brazil
PMID# 15691289
Abstract

The objective of this case report is to document the possibility that ImmunoAblative doses of Cyclophosphamide may provide a long-term remission of Multiple Sclerosis (MS).

We report the case of a 48-year-old woman with Definite MS diagnosed in 1994 who has been in complete remission since a dose of 3800 mg of Cyclophosphamide was accidentally given intravenously in early 1997.

For 7 years there have been no signs of disease activity on history, physical examination, or on high-quality Magnetic Resonance Imaging (MRI) with appropriate contrast-enhancement methodology.

This case includes information on the possibility that less aggressive ChemoTherapy than that used with Stem Cell Transplantation may be effective in the long-term control of MS.



#10

Cyclophosphamide Is Effective In Stabilizing Rapidly Deteriorating Secondary/Progressive Multiple Sclerosis

Perini P, Gallo P
J Neurol 2003 Jul;250(7):834-8
Multiple Sclerosis Center, First Neurology Clinic, Department of Neurological & Psychiatrical Sciences, University of Padova, Via Giustiniani 5, 35128 Padova, Italy
PMID# 12883926
Abstract

The safety and efficacy of pulse Cyclophosphamide (CTX) therapy was investigated in patients with very active Secondary/Progressive Multiple Sclerosis, characterized by frequent relapses and rapid disability progression.

For this purpose the clinical and MRI effects were assessed.

Sixteen patients, 11 female and 5 male, were experiencing rapidly deteriorating disease, characterized by frequent and severe relapses as well as rapid progression (defined by an increase of more than 1 EDSS point in a period of 1 year).

Mean relapse rate in the two years preceding CTX therapy was 3.0 +/-1.4. Mean EDSS was 4.0+/-1.4 one year before therapy and 5.6+/-1.0 at study entry.

Treatment consisted in administration of high dose intravenous CTX every four weeks for one year and then every eight weeks for an additional twelve months.

CTX dose was tailored to the patient's white blood cell response, and ranged from 800 to 1,200 mg/m(2) body surface. MRI was performed before therapy and then at 12 (Y1) and 24 (Y2) months.

Eight patients with similar clinical features constituted a control group. CTX therapy was safe and well tolerated, and no severe side effects were observed.

The EDSS decreased to 4.3+/-1.6 at Y1 (Y0 vs.Y1: p< 0.001) and to 4.1+/-1.6 at Y2 (Y0 vs.Y2: p< 0.001). Only four patients experienced relapses during the first year of therapy, while no relapses were observed during the second year of therapy.

The mean relapse rate during therapy was 0.25 +/-0.45 (p< 0.0001).No increase in T2 lesion load was observed over the two years.

A significant clinical and MRI deterioration was observed in the control group. Therapy with pulse CTX was able to stop disease activity and progression in patients with rapidly evolving Secondary/Progressive MS.



#11

Treatment Of Progressive Forms Of Multiple Sclerosis By Cyclophosphamide: A Cohort Study Of 490 Patients

Zephir H, de Seze J, Duhamel A, Debouverie M, Hautecoeur P, Lebrun C, Malikova I, Pelletier J, Senechal O, Vermersch P
J Neurol Sci 2004 Mar 15;218(1-2):73-7
Hopital R. Salengro, CHRU of Lille, Department of Neurology, 59037, Lille, cedex, France
PMID# 14759636
Abstract

There are no generally effective disease-modifying drugs for Progressive forms of Multiple Sclerosis (MS). Some MS centres use Cyclophosphamide (CYC) in Secondary/Progressive (SP) forms of MS, especially after Interferon-beta-1b (INF-beta-1b) treatment failure.

Moreover, there are currently no approved drugs for Primary/Progressive (PP MS). Using the collected data of patients with Progressive MS, we studied clinical patterns that predicted a good response to CYC treatment.

Secondly, we compared the therapeutic response of SPMS and PPMS patients to the treatment. Data from 490 MS patients were collected.

All patients presented an SP (n = 362) or PP (n = 128) form of the disease and 476 had been treated for at least one year with a monthly pulse of CYC associated with MethylPrednisolone (MP).

CYC treatment was justified because of at least a 1-point worsening on the Expanded Disability Status Scale (EDSS) during the previous year.

The EDSS score was assessed at baseline and after 6 months (M6) and 12 months (M12) of treatment.

After 12 months of CYC treatment, 78.6% of SPMS and 73.5% of PPMS patients had stabilized or had an improved EDSS score. Response to CYC was not significantly different in the two Progressive forms of MS.

Twenty-two patients presented noticeable drug side effects, one of whom withdrew from the treatment due to intolerance.

Patients with an improved EDSS at M12 had a shorter mean progressive time course (5.1 years) than patients who stabilized or worsened (7.1 years) (p = 0.02). We also observed that poor responders at M6 were also poor responders at M12 (p < 0.001).

This large cohort study showed that CYC treatment was well tolerated and suggested that a better response occurred in cases with a short progressive time course.

We did not find any difference in treatment response between the two Progressive forms of MS.

To date, no treatment is approved for PPMS and we therefore propose a trial to test the use of CYC treatment early in the course of the disease in PPMS patients with disability progression.



#12

Treatment Of Progressive Multiple Sclerosis With Monthly Pulsed Cyclophosphamide-MethylPrednisolone: Predictive Factors Of Treatment Response

Delmont E, Chanalet S, Bourg V, Soriani MH, Chatel M, Lebrun C
Rev Neurol (Paris) 2004 Jul;160(6-7):659-65
Service de Neurologie, CHU de Nice
PMID# 15247854
Abstract

Introduction
Cyclophospamide is used in the treatment of Progressive Multiple Sclerosis. We were looking for predictive indicators of treatment response.

Material And Methods
Forty-seven patients with Secondary Progressive Multiple Sclerosis and seven others with Primary/Progressive received monthly infusions of Cyclophosphamide (750mg/m2) and MethylPrednisolone (500mg).

During the year before Cyclophosphamide the EDSS had worsened one point in all patients with or without surimposed relapses. Evaluation was based on EDSS change at 6, 12, 24 months and 5 years.

Results
Among Secondary/Progressive patients, 91 per 100 (43/47) were stable or improved at 12 months, 65 per 100 (26/40) at 24 months and 22 per 100 (5/23) at 5 years.

Annual relapse rate decreased from 0.81 before treatment to 0.48 during treatment and 0.12 after treatment (p<0.001).

At 24 months, efficacy was correlated to a progressive phase lasting less than 5 years (p< 0.01) and to a rapid increase of EDSS of at least 2 points the year before treatment (p< 0.05).

There were no influences of age, EDSS and surimposed relapses at the beginning of treatment, and other immunoactive drugs administrated before Cyclophosphamide.

There was no significant difference in quality of response to treatment between patients with primary progressive and Secondary/Progressive Multiple Sclerosis.

Conclusion
Cyclophosphamide appears to be more efficient in early stage of Progressive Multiple Sclerosis independently of age, relapses or Neurological disability scale.



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