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DHAP

Cancer Type: Hematologic, Lymphoma - Hodgkin, Lymphoma - Non-Hodgkin's High Grade, Lymphoma - Non-Hodgkin's Intermediate Grade  Intent: Curative
Regimen Category: Evidence-Informed
Funding:
ODB - General Benefit
    dexamethasone
A - Regimen Name

DHAP Regimen
Dexamethasone-High dose ARA-C (Cytarabine)-PLATINOL® (CISplatin)


Disease Site
Hematologic - Lymphoma - Hodgkin
Hematologic - Lymphoma - Non-Hodgkin's High Grade
Hematologic - Lymphoma - Non-Hodgkin's Intermediate Grade

Intent
Curative

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

For treatment of relapsed / refractory aggressive non-Hodgkin's lymphoma or Hodgkin's lymphoma, prior to autologous stem cell transplant (ASCT).


Supplementary Public Funding

dexamethasone
ODB - General Benefit (dexamethasone) (

tablets

)

 
B - Drug Regimen

Adapted for outpatient administration

CISplatin
100 mg /m² IV Day 1
cytarabine
2000 mg /m² IV over 2 hours Q12H on Day 2
dexamethasone
40 mg PO Days 1 to 4
(Outpatient prescription in multiples of 4mg tablets)
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C - Cycle Frequency

REPEAT EVERY 21 TO 28 DAYS

After 2-3 cycles, responding patients may be considered for high-dose chemotherapy and autologous stem cell transplant.

Patients with stable disease who were not candidates for stem cell transplant or patients who had any response after 2-3 cycles of DHAP may receive up to 6 cycles of treatment.

 
D - Premedication and Supportive Measures

Antiemetic Regimen:

High


Febrile Neutropenia Risk:

High

Other Supportive Care:

Also refer to CCO Antiemetic Summary

Standard regimens for Cisplatin premedication and hydration should be followed. Refer to local guidelines.

Cytarabine: dexamethasone eye drops 0.1% - instill 2 drops in each eye q 6 hour x 4 doses beginning 1 hour before the first dose of cytarabine, for 2 days.

 
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 the LY12 protocol (Crump 2014).

Dosage with toxicity

Since this regimen is used as salvage therapy for potentially curative intent, it is recommended that modification of this regimen be done only after discussion with a medical oncologist experienced in the treatment of lymphoma.

Dosage with Hematologic Toxicity:

Blood counts on day 1

 

Blood counts on day 1

Cytarabine and cisplatin dose for this cycle

ANC ≥ 1

and

Platelets < 75

Delay 1 week*  Restart at same dose if platelets ≥ 751

If platelets 50 to <75 after 1 week, may restart at same dose with platelet support as necessary1

ANC < 1

and

Platelets ≥ 75

Delay 1 week*  Restart at same dose if ANC ≥ 11

If ANC ≥0.5 to <1, restart at same dose with G-CSF** support1

ANC < 1

and

 Platelets < 75

Delay 1 week*

After 1 week, if ANC > 0.5 and platelets > 50, restart at same dose with GCSF** and platelet support1

OR

If ANC < 0.5 and/ or platelets < 50, check counts q 3-4 days. When both ANC 0.5 and platelets 50, restart at same dose and with GCSF** and platelet support1

 

*If counts presumed to be low due to marrow involvement, treat after 1-week delay (e.g. at 4 weeks or Day 28) despite counts.

** GCSF should be given prophylactically for all future cycles 

1 Crump et al 2014

 

Dosage with Non-Hematologic Toxicity:

 

Worst Toxicity in Previous Cycle

Cisplatin (% previous dose)* for this cycle

Cytarabine (% previous dose) for this cycle*

Dexamethasone

Grade 3 related non-hematologic toxicity, except nausea, vomiting, alopecia

Hold*, then 75%1

Hold*, then 75%1

No change

Creatinine 1.5 to 3 x ULN

75%

No change

No change

Grade 3 or 4 neurotoxicity /ototoxicity

(cerebellar/ gait dysfunction related to cytarabine; sensory/peripheral)

Discontinue

Discontinue1

Discontinue

Other grade 4 non-hematologic/organ toxicity or creatinine > 3 x ULN

Hold for one week, hydrate.  Discontinue if it does not resolve to ≤ grade 21

Hemolysis, optic neuritis, arterial thromboembolism, severe hypersensitivity reactions

Discontinue

Discontinue

Discontinue

1 Crump et al 2014

† If toxicity is related to dexamethasone, may consider holding this drug for this cycle then re-assess for future cycles.

 



Hepatic Impairment

No dosage adjustment required for cisplatin. Cytarabine dose should be reduced with impaired hepatic function; no details available.


 


Renal Impairment

For cisplatin, renal function should have normalized before patients are retreated. If continued treatment is considered to be mandatory, the following dose modifications could be considered at the physician's discretion (Kintzel 1995).

Creatinine clearance
Cisplatin (% previous dose)
46-60
75%
30-45
50%
<30
Discontinue

 

For cytarabine, no adjustment required for standard doses.  For high-dose therapy, since renal impairment (< 60 mL/min) is a risk factor for neurotoxicity, consider:

  • dose reduction (2 g/m2→  1 g/m2→ 0.1 g/m2/day CIV)
  • schedule modification (i.e. from q12h to q24h)

 

Dosage in the elderly

Geriatric patients may be at higher risk of developing nephrotoxicity, ototoxicity, neurotoxicity or hematologic adverse effects.

 


 
F - Adverse Effects

Refer to CISplatin, cytarabine, dexamethasone 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 / bleeding (may be severe)
  • Nausea and vomiting
  • Rash (may be severe)
  • Mucositis
  • Diarrhea (may be severe colitis)
  • Flu-like symptoms
  • ↑ LFTs
  • Hand-foot syndrome (may be severe)
  • Nephrotoxicity (may be severe)
  • Electrolyte abnormalities
  • Neurotoxicity and ototoxicity (may be severe)
  • Reproductive risk
  • Steroid effects (weight gain, myopathy, cataracts, hyperglycemia, gastric irritation, insomnia, mood changes, osteoporosis)
  • Alopecia
  • Fatigue
  • Anorexia
  • Conjunctivitis
  • Arterial thromboembolism
  • Venous thromboembolism
  • Arrhythmia
  • Hemolytic uremic syndrome
  • Secondary malignancies
  • Hypersensitivity
  • Hemolysis
  • Optic neuritis
  • Vasculitis
  • Pancreatitis
  • Leukoencephalopathy
  • ARDS, pneumonitis
  • Tumor lysis syndrome
  • GI perforation
  • Thrombotic angiopathy
  • Syncope
  • SIADH
 
G - Interactions

Refer to CISplatin, cytarabine, dexamethasone drug monograph(s) for additional details


  • Avoid nephrotoxic and ototoxic drugs (i.e. aminoglycosides) due to additive effects.
  • Concomitant use of renally excreted drugs (i.e. methotrexate) may decrease renal clearance and enhance toxicities of these drugs.  Avoid use, if possible.  If not possible, modify doses as necessary.
  • Cisplatin may decrease phenytoin levels; monitor levels and patient.
  • Cytarabine can decrease the efficacy of digoxin; monitor levels
  • Cytarabine can decrease the effect of flucytosine; the dose of flucytosine should be increased
  • Methotrexate IT can cause an increased risk of severe neurological effects when given with cytarabine IV; avoid concomitant administration
  • Cyclophosphamide can cause increased cardiomyopathy and sudden death with high dose cytarabine; avoid the combination
 
H - Drug Administration and Special Precautions

Refer to CISplatin, cytarabine, dexamethasone drug monograph(s) for additional details


Administration

Cisplatin:

  • Ensure good urinary output during chemotherapy visit.  Patient should void at least once during chemotherapy visit.  Use locally approved hydration regimens.
  • Blood pressure should be taken before and after chemotherapy.
  • Additional hydration may be ordered for hypovolemic patients.
  • Hydration and diuresis for patients with pre-existing renal, cardiac, or diabetic history at discretion of physician.
  • Oral hydration with 8 glasses of fluid per day is strongly encouraged on treatment day and for 1-2 days after cisplatin; if nausea and vomiting prevent oral hydration, the patient may need to return for more IV hydration.
  • Cisplatin is physically incompatible with any IV set, needle or syringe containing aluminum.
  • Store unopened vials between 15°C to 25°C and protect from light.  Do not refrigerate or freeze since precipitation will occur.

Cytarabine:

  • May be mixed in 250mL bag (Normal Saline – preferred, or 5% dextrose)
  • DO NOT use benzyl alcohol diluent with high dose cytarabine
  • Incompatible with heparin, insulin, 5-fluorouracil, penicillin G and methylprednisolone sodium succinate.

Contraindications:

  • patients with known hypersensitivity to cytarabine or platinum containing compounds
  • patients who are severely myelosuppressed
  • patients with pre-existing renal impairment and hearing impairment, unless the possible benefits of treatment outweigh the risks. 

 

Other Warnings/Precautions:

  • All patients should receive appropriate hydration and antiemetic protocols according to local guidelines.
  • Extreme caution should be used with high dose cytarabine therapy, especially in older patients, patients with hepatic or renal impairment, pre-existing CNS, cardiovascular or pulmonary disease.
  • Avoid live vaccines
  • Cisplatin and cytarabine are not recommended for use in pregnancy or breastfeeding.  Appropriate contraception should be used by both sexes during treatment, and for at least 6 months after the last dose (general recommendation)  
 
I - Recommended Clinical Monitoring

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

Note: high dose cytarabine regimens require intensive monitoring

Recommended Clinical Monitoring

  • CBC; Baseline, and before each cycle (weekly is suggested)
  • Liver function tests; Baseline and before each cycle
  • Renal function tests; Baseline and before each cycle
  • Electrolytes, including magnesium, sodium, potassium, phosphate and calcium; Baseline and before each cycle
  • Audiogram; Baseline and as clinically indicated
  • Clinical toxicity assessment of infection, bleeding, nausea/vomiting, neurotoxicity, ototoxicity, thromboembolism, GI, CNS, pulmonary, skin and ocular toxicity; 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
Inpatient regimen; some centres have modified this regimen for outpatient treatment.
Pharmacy Workload (average time per visit)
28.583 minutes
Nursing Workload (average time per visit)
44.167 minutes
 
K - References

Cisplatin and cytarabine drug monographs, Cancer Care Ontario.

Crump M, Kuruvilla J, Couban S, et al. Randomized comparison of gemcitabine, dexamethasone, and cisplatin versus dexamethasone, cytarabine, and cisplatin chemotherapy before autologous stem-cell transplantation for relapsed and refractory aggressive lymphomas: NCIC-CTG LY.12. J Clin Oncol 2014 Nov 1;32(31):3490-6.

Mey UJ, Olivieri A, Orlopp KS, et al. DHAP in combination with rituximab vs DHAP alone as salvage treatment for patients with relapsed or refractory diffuse
large B-cell lymphoma: a matched-pair analysis. Leuk Lymphoma. 2006 Dec;47(12):2558-66.

Olivieri A, Brunori M, Capelli D, et al. Salvage therapy with an outpatient DHAP schedule followed by PBSC transplantation in 79 lymphoma
patients: an intention to mobilize and transplant analysis. Eur J Haematol. 2004 Jan;72(1):10-7.

Press OW, Livingston R, Mortimer J, et al. Treatment of relapsed non-Hodgkin's lymphomas with dexamethasone, high-dose cytarabine, and cisplatin before marrow transplantation. J Clin Oncol 1991 Mar;9(3):423-31.

Velasquez WS, Cabanillas F, Salvador P, et al. Effective salvage therapy for lymphoma with cisplatin in combination with high-dose Ara-C and dexamethasone (DHAP). Blood. 1988 Jan;71(1):117-22.

Witzig TE, Geyer SM, Kurtin PJ, et al. Salvage chemotherapy with rituximab DHAP for relapsed non-Hodgkin lymphoma: a phase II trial in the North Central Cancer Treatment Group. Leuk Lymphoma 2008 Jun;49(6):1074-80.

March 2018 Modified cycle frequency section


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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.