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A - Regimen Name

FCM Regimen
Fludarabine-Cyclophosphamide-mitoXANTRONE


Disease Site
Hematologic - Lymphoma - Non-Hodgkin's Low Grade

Intent
Palliative

Regimen Category
Evidence-Informed :

Regimen is considered appropriate as part of the standard care of patients; meaningfully improves outcomes (survival, quality of life), tolerability or costs compared to alternatives (recommended by the Disease Site Team and national consensus body e.g. pan-Canadian Oncology Drug Review, pCODR).  Recommendation is based on an appropriately conducted phase III clinical trial relevant to the Canadian context OR (where phase III trials are not feasible) an appropriately sized phase II trial. Regimens where one or more drugs are not approved by Health Canada for any indication will be identified under Rationale and Use.


Rationale and Uses

Treatment of recurrent follicular or other non-Hodgkin’s indolent B-cell lymphoma 


Supplementary Public Funding

fludarabine
New Drug Funding Program (Fludarabine - Indolent Lymphoma) (NDFP Website)

 
B - Drug Regimen

fludarabine

(Round to nearest 2.5 mg)
25 mg /m² IV Days 1 to 3
cyclophosphamide

(Round to nearest 10 mg)
200 to 250 mg /m² IV Days 1 to 3
mitoXANTRONE

(Round to nearest 1 mg)
6 mg /m² IV Day 1 ONLY
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C - Cycle Frequency

REPEAT EVERY 28 DAYS

For a usual total of 6 cycles unless disease progression or unacceptable toxicity occurs

 
D - Premedication and Supportive Measures

Antiemetic Regimen:

Moderate

Other Supportive Care:

Also refer to CCO Antiemetic Summary

  • If high volume disease (e.g. WBC > 25 x 109/L), consider prophylaxis for tumour lysis
  • Consider prophylactic growth factor support, antiviral and PCP prophylaxis (according to local practice)
 
E - Dose Modifications

Doses should be modified according to the protocol by which the patient is being treated. The following recommendations have been adapted from clinical trials or product monographs and could be considered.

Dosage with toxicity

Suggested dose levels for fludarabine are 25, 20 and 15 mg/m2
Suggested dose levels for cyclophosphamide are 200 and 150 mg/m2
Suggested dose levels for mitoxantrone are 6, 4.5 and 3 mg/m2
 
Toxicity
Fludarabine
(% previous dose)
Cyclophosphamide
(% previous dose)
Mitoxantrone
(% previous dose)
Febrile Neutropenia;
Grade 4 myelosuppression  ≥ 7 days; Thrombocytopenic bleeding;
1-2 week delay prior cycle
↓ 1 dose level or
G-CSF (for isolated neutropenia)*
↓ 1 dose level or
G-CSF (for isolated neutropenia)*
↓ 1 dose level or
G-CSF (for isolated neutropenia)*
Grade 3 non-hematologic/organ
 
↓ 1 dose level*
↓ 1 dose level*
↓ 1 dose level*
Grade 4 non-hematologic /organ
 
Discontinue
Discontinue
Discontinue
Any grade autoimmune, neurotoxicity, pneumonitis, cardiotoxicity,
> 2 week delay prior cycle
Discontinue
Discontinue
Discontinue
*Do not retreat until non-hematologic/ organ toxicity recovered to ≤ grade 2, ANC to ≥ 1.5 x 109/L and platelets ≥ 100 x 109/L (or to baseline levels).



Hepatic Impairment

AST/ALT
 
Bilirubin
Mitoxantrone (% previous dose)
 
Fludarabine
(% previous dose)
Cyclophosphamide
(% previous dose)
3-5 X ULN
And/or
1-2 x ULN
↓ 50%
No data; use with caution
No change
>5 x ULN
And/or
> 2-3 x ULN
Discontinue
 
Caution

Renal Impairment

Creatinine Clearance (mL/min)
Mitoxantrone (% previous dose)
Fludarabine
(% previous dose)
Cyclophosphamide
(% previous dose)
> 50 – 70
No change
50%
100%
30 - 50
75%
10 - <30
Discontinue
75%
< 10

Use with extreme caution or Discontinue


 
F - Adverse Effects

Refer to fludarabine, cyclophosphamide, mitoXANTRONE drug monograph(s) for additional details of adverse effects


Most Common Side Effects

Less Common Side Effects, but may be Severe or Life-Threatening

          

  • Myelosuppression ± infection (including opportunistic), bleeding (may be severe)
  • GI (nausea/vomiting, stomatitis, diarrhea, anorexia, constipation)
  • Fever, flu-like symptoms
  • Edema
  • Fatigue
  • Rash (may be severe)
  • Visual changes
  • Cystitis
  • Alopecia
  • ↑ LFTs

 

  • Autoimmune disorders (e.g. hemolytic anemia, TTP)
  • Encephalopathy, CNS toxicity (e.g. seizures, confusion, agitation)
  • Pneumonitis
  • Cardiotoxicity, arrhythmia
  • Arterial thromboembolism
  • Venous thromboembolism
  • Secondary malignancies
  • Tumour lysis syndrome
  • Pancreatitis
  • Rhabdomyolysis
  • Nephrotoxicity
 
G - Interactions

Refer to fludarabine, cyclophosphamide, mitoXANTRONE drug monograph(s) for additional details

 
H - Drug Administration and Special Precautions

Refer to fludarabine, cyclophosphamide, mitoXANTRONE drug monograph(s) for additional details

 
I - Recommended Clinical Monitoring

Recommended Clinical Monitoring

  • CBC; baseline and at each visit
  • Renal (including urinalysis) and liver function tests; baseline and at each visit
  • Baseline and regular cardiac examination for patients with cardiac risk factors (including prior therapy with Epirubicin, Doxorubicin, or other cardiotoxic drug), and cumulative mitoxantrone doses > 140mg/m 2
  • Clinical toxicity assessment (including hypersensitivity, CNS toxicity, cardiotoxicity, infection, bleeding, GI, skin and pulmonary toxicity, tumour lysis syndrome, thromboembolism, cystitis); at each visit
  • Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version


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J - Administrative Information

Approximate Patient Visit
1.5 hours
Pharmacy Workload (average time per visit)
26.168 minutes
Nursing Workload (average time per visit)
45 minutes
 
K - References

Forstpointner R, Dreyling M, Repp R, et al; German Low-Grade Lymphoma Study Group. The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood. 2004 Nov 15;104(10):3064-71.

Fludarabine, cyclophosphamide, mitoxantrone drug monographs, Cancer Care Ontario.

Hendry L, Bowen A, Matutes E, et al. Fludarabine, cyclophosphamide and mitoxantrone in relapsed or refractory chronic lymphocytic leukemia and low grade non-Hodgkin's lymphoma. Leuk Lymphoma. 2004 May;45(5):945-50.

Santini G, Nati S, Spriano M, Gallamini A, Pierluigi D, Congiu AM, Truini M, Rubagotti A, Chisesi T, Vimercati R, Rossi E, Sertoli MR, Mattei D, Marino G, Gobbi M. Fludarabine in combination with cyclophosphamide or with cyclophosphamide plus mitoxantrone for relapsed or refractory low-grade non-Hodgkin's lymphoma. Haematologica. 2001 Mar;86(3):282-6.

October 2017 Replaced regimen category with evidence-informed


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M - Disclaimer

Regimen Abstracts
A Regimen Abstract is an abbreviated version of a Regimen Monograph and contains only top level information on usage, dosing, schedule, cycle length and special notes (if available). It is intended for healthcare providers and is to be used for informational purposes only. It is not intended to constitute or be a substitute for medical advice, and all uses of the Regimen Abstract are subject to clinical judgment. Such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability, and Cancer Care Ontario disclaims all liability for the use of this information, and for any claims, actions, demands or suits that arise from such use.
Information in regimen abstracts is accurate to the extent of the ST-QBP regimen master listings, and has not undergone the full review process of a regimen monograph.  Full regimen monographs will be published for each ST-QBP regimen as they are developed.
Regimen Monographs
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.
The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.
Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.
While care has been taken in the preparation of the information contained in the Formulary, such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability.
CCO and the Formulary’s content providers shall have no liability, whether direct, indirect, consequential, contingent, special, or incidental, related to or arising from the information in the Formulary or its use thereof, whether based on breach of contract or tort (including negligence), and even if advised of the possibility thereof. Anyone using the information in the Formulary does so at his or her own risk, and by using such information, agrees to indemnify CCO and its content providers from any and all liability, loss, damages, costs and expenses (including legal fees and expenses) arising from such person’s use of the information in the Formulary.