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14.1 rituximab

Refer to the FDA approved package insert for complete product information.
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14.1.1 supply

Genentech/IDEC will supply the agent for this protocol to DFCI, MGH, BIDMC and MD Anderson Cancer Center. It is otherwise commercially available. Rituximab is provided in pharmaceutical grade glass vials containing 10 mL (100 mg) or 50 mL (500 mg) at a concentration of 10 mg of protein per milliliter. Please refer to the FDA-approved package insert for rituximab for product information, extensive preparation instructions, and a comprehensive list of adverse events. 14.1.2 Storage Rituximab for clinical use should be stored in a secure refrigerator at 2º to 8°C.
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1 4. 1. 3 pre

Rit u xi ma b will be dil ute d wit h 0. 9 % S o di u m C hl ori de or 5 % De xtr ose I njecti o n t o pre pare a sta n dar d pr o d uct wit h c o nce ntrati o n of 2 m g/ ml. Ca uti o n s h o ul d be ta ke n d uri n g t he pre parati o n of t he dr u g, as s ha ki n g ca n ca use a g gre gati o n a n d preci pitati o n of t he a nti b o d y 1 4. 1. 4 Sta bilit y After dil uti o n, rit u xi ma b is sta ble at 8 de grees C ( 3 6 4 6 de grees F) f or 2 4 h o urs a n d at r o o m te m perat ure f or a n a d diti o nal 2 4 h o urs.
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1 4. 1. 5 a

A peri p heral or ce ntral i ntra ve n o us li ne will be esta blis he d. D uri n g rit u xi ma b i nf usi o n, a patie nt's vital si g ns ( bl o o d press ure, p ulse, res pir ati o n, te m perat ure) s h o ul d be m o nit ore d acc or di n g t o t he sta n dar d of care. Me dicati o ns rea dil y a vaila ble f or t he e mer ge nc y ma na ge me nt of a na p h ylact oi d reacti o ns s h o ul d i ncl u de: e pi ne p hri ne ( 1: 1 0 0 0, 1 m g/ m L) f or s u bc uta ne o us i njecti o n, di p he n h y dra mi ne h y dr o c hl ori de f or i ntra ve n o us i njecti o n, a n d res uscitati o n e q ui p me nt.  
Pr o p h yla xis a gai nst h y perse nsiti vit y a n d i nf usi o n relate d reacti o ns ass ociate d wit h rit u xi ma b will i ncl u de aceta mi n o p he n 6 5 0 m g a n d di p he n h y dra mi ne h y dr oc hl ori de 5 0 1 0 0 m g a d mi nistere d 3 0 t o 6 0 mi n utes pri or t o starti n g rit u xi ma b. Patie nts will als o recei ve t heir first d ose of pre d nis o ne 6 0 m g/ m 2 ( or a gl uc oc ortic oi d e q ui vale nt d ose of a n alter nati ve ster oi d) at least 6 0 mi n utes bef ore rit u xi ma b treat me nt c o m me nces.  
Rit u xi ma b will be a d mi niste re d as a n i ntra ve n o us i nf usi o n at 3 7 5 m g/ m 2 o n da y 1 of eac h c ycle of E P O C H, i m me diatel y pri or t o starti n g et o p osi de + d o x or u bici n + vi ncristi ne a d mi nistrati o n.  
F or L o w Ris k Patie nts recei vi n g E P O C H R R, Rit u xi ma b will als o be a d mi nistere d o n da y 5 of eac h c ycle, f oll o wi n g et o p osi de + d o x or u bici n + vi ncristi ne b ut pri or t o c ycl o p h os p ha mi de a d mi nistrati o n . Rit u xi ma b i nf usi o ns will be a d mi nistere d t o patie nts pri maril y i n a n o ut patie nt cli nic setti n g.
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first d ose

T he i nitial d ose rate at t he ti me of t he firs t rit u xi ma b i nf usi o n s h o ul d be 5 0 m g/ h o ur ( 2 5 m L/ hr)  
f or t he first 3 0 mi n utes. If n o t o xicit y is see n, t he d ose rate ma y be escalate d gra d uall y i n 5 0 m g/ h o ur ( 2 5 m L/ h) i ncre me nts at 3 0 mi n ute i nter vals) t o a ma xi m u m of 4 0 0 m g/ h o ur ( ma xi m u m rate = 2 0 0 m L/ h).
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9 0 mi n ute

If t he first d ose of rit u xi ma b was well t olerate d, s u bse q ue nt d oses ma y be a d mi nistere d o ver 9 0 mi n utes wit h 2 0 % of t he t otal d ose gi ve n i n t he first 3 0 mi n utes, a n d re mai ni n g 8 0 % of t he t otal d ose a d mi nistere d o ver t he s u bse q ue nt 6 0 mi n utes; e. g.:  
| T w o               | Ste p Rate Escalati o n   | V ol u me t o a d mi nister ( X   | m L)   |                   |       |
|---------------------|---------------------------|-----------------------------------|--------|-------------------|-------|
| T otal D ose ( m g) |                           |                                   |        |                   |       |
| 1st p orti o n ( 0  | 3 0 mi n utes)            |                                   | 0. 2   | X m L ( o ver 3 0 | mi n) |  
| T otal D ose ( m g)    |                |      |                   |       |
|------------------------|----------------|------|-------------------|-------|
| 2 n d p orti o n ( 3 0 | 9 0 mi n utes) | 0. 8 | X m L ( o ver 6 0 | mi n) |  
S peci al N ote : T he 9 0 mi n ute i nf usi o n sc he me is n ot rec o m me n de d f or patie nts wit h cli nicall y si g nifica nt car di o vasc ular disease or hi g h circ ulati n g l y m p h oc yte c o u nts ( 5 0 0 0/ mc L).
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st a n d ar

Patie nts w h o t olerate i nitial treat me nt wit h o ut e x perie nci n g i nf usi o n relate d a d verse effects b ut f or w h o m t he 9 0 mi n ute i nf usi o n sc he me d uri n g s u bse q ue nt treat me nts is c o nsi dere d i na p pr o priate, ma y recei ve s u bse q ue nt rit u xi ma b d oses at t he Sta n dar d Rate for S u bse q ue nt I nf usi o ns, w hic h is as f oll o ws:  
Be gi n at a n i nitial rate of 1 0 0 m g/ h o ur ( 5 0 m L/ h) f or 3 0 mi n utes. If a d mi nistrati o n is well t olerate d, t he a d mi nistrati o n rate ma y be escalate d gra d uall y i n 1 0 0 m g/ h o ur ( 5 0 m L/ h) at 3 0 mi n ute i nter vals t o a ma x i m u m rate of 4 0 0 m g/ h o ur ( ma xi m u m rate = 2 0 0 m L/ h).  
C A U TI O N: D O N O T A D MI NI S T E R A S A N I N T R A V E N O U S P U S H O R B O L U S.  
1 4. 1. 6 Safet y Pr ofile N o d ose li miti n g effects were o bser ve d i n t he P hase I/II st u dies. Re p orte d a d verse e ve nts i ncl u di n g fe ver, c hills, hea dac he, na usea, v o miti n g, r hi nitis, ast he nia, a n d h y p ote nsi o n, occ urre d pri maril y d uri n g rit u xi ma b i nf usi o ns a n d t y picall y res p o n de d t o a n i nterr u pti o n of t he i nf usi o n a n d res u m pti o n at a sl o wer rate.  
Fatal I nf usi o n Reacti o ns: Se vere a n d fatal car di o p ul m o nar y e ve nts, i ncl u di n g a n gi oe de ma, h y p o xia, p ul m o nar y i nfiltrates, ac ute res pirat or y distress s y n dr o me, m y ocar dial i nfarcti o n, a n d car di o ge nic s h oc k, ha ve bee n re p orte d. T hese se vere reacti o ns t y picall y occ urre d d uri n g t he first i nf usi o n wit h ti me t o o nset of 3 0 1 2 0 mi n utes.  
Car diac E ve nts: Patie nts wit h pree xisti n g car diac c o n diti o ns, i ncl u di n g arr h yt h mia a n d a n gi na, ha ve ha d rec urre nce s of t hese car diac e ve nts d uri n g rit u xi ma b i nf usi o ns.  
T u m or L ysis S y n dr o me: T u m or l ysis s y n dr o me, s o me wit h fatal o utc o me, has bee n re p orte d a n d is c haracterize d i n patie nts wit h a hi g h n u m ber of circ ulati n g mali g na nt cells ( ≥ 2 5, 0 0 0 ul) b y ra pi d re d ucti on i n t u m or v ol u me, re nal i ns ufficie nc y, h y per kale mia, h y p ocalce mia, h y per urice mia, a n d h y per p h os p hate mia.  
Re nal E ve nts: Rit u xi ma b has bee n ass ociate d wit h se vere re nal t o xicit y i ncl u di n g ac ute re nal fail ure re q uiri n g dial ysis, a n d i n s o me cases has le d t o deat h. Re nal t o xicit y has occ urre d i n patie nts wit h hi g h n u m bers of circ ulati n g mali g na nt cells ( ≥ 2 5, 0 0 0/ m m 2 ) or hi g h t u m or b ur de n w h o e x perie nce t u m or l ysis s y n dr o me a n d i n patie nts a d mi nistere d c o nc o mita nt cis plati n.  
M uc oc uta ne o us Reacti o ns: Se vere b ull o us s ki n reacti o ns, i ncl u di n g fatal cases of t o xic e pi der mal necr ol ysis a n d para ne o plastic pe m p hi g us, ha ve bee n re p orte d i n patie nts treate d wit h rit u xi ma b. T he o nset of reacti o n has varie d fr o m 1 t o 1 3 wee ks f oll o wi n g rit u xi ma b e x p os ure.  
He mat ol o gic E ve nts: I n cli nical trials, Gra de 3 a n d 4 c yt o pe nias were re p orte d i n 4 8 % of patie nts treate d wit h rit u xi ma b; t hese i ncl u de: l y m p h o pe nia ( 4 0 %), ne utr o pe nia ( 6 %), le u k o pe nia  
( 4 %), a ne mia ( 3 %), a n d t hr o m b oc yt o pe nia ( 2 %). T he me dia n d urati o n of l y m p h o pe nia was 1 4 da ys (ra n ge, 1 t o 5 8 8 da ys) a n d of ne utr o pe nia was 1 3 da ys (ra n ge, 2 t o 1 1 6 da ys). A si n gle occurrence of transient aplastic anemia (pure red cell aplasia) and two occurrences of hemolytic anemia following Rituximab therapy were reported. In addition, there have been a limited number of post-marketing reports of prolonged pancytopenia, marrow hypoplasia, and late onset neutropenia. Infectious Events: Rituxan induced B-cell depletion in 70% to 80% of patients with NHL and was associated with decreased serum immunoglobulins in a minority of patients; the lymphopenia lasted a median of 14 days (range, 1-588 days). Infectious events occurred in 31% of patients: 19% of patients had bacterial infections, 10% had viral infections, 1% had fungal infections, and 6% were unknown infections. Serious infectious events (Grade 3 or 4), including sepsis, occurred in 2% of patients. Hepatitis B Reactivation: Hepatitis B virus (HBV) reactivation with fulminant hepatitis, hepatic failure, and death has been reported in some patients with hematologic malignancies treated with rituximab. The majority of patients received rituximab in combination with chemotherapy. The median time to the diagnosis of hepatitis was approximately four months after the initiation of rituximab and approximately one month after the last dose. Other Serious Viral Infections: The following additional serious viral infections, either new, reactivated or exacerbated, have been identified in clinical studies or post-marketing reports. The majority of patients received Rituxan in combination with chemotherapy or as part of a hematopoietic stem cell transplant. These viral infections included JC virus (progressive multifocal leukoencephalopathy [PML]), cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis C. In some cases, the viral infections occurred up to one year following discontinuation of Rituxan and have resulted in death.
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progressive multifocal leukoencephalopathy (pml)

PML is a rare disease caused by the reactivation of latent JC virus in the brain. Immunosuppression allows reactivation of the JC virus which causes demyelination and destruction of oligodendrocytes resulting in death or severe disability. Rare cases of PML, some resulting in death, have been reported in patients with hematologic malignancies who have received rituximab. The majority of these patients had received rituximab in combination with chemotherapy or as part of a hematopoietic stem cell transplant. Cases of PML resulting in death have also been reported following the use of rituximab for the treatment of autoimmune diseases. The reported cases had multiple risk factors for PML, including the underlying disease and long-term immunosuppressive therapy or chemotherapy. Most cases of PML were diagnosed within 12 months of their last infusion of rituximab. Physicians should consider PML in any patient presenting with new onset neurologic manifestations. Consultation with a neurologist, brain MRI, and lumbar puncture should be considered as clinically indicated. In patients who develop PML, rituximab should be discontinued and reductions or discontinuation of any concomitant chemotherapy or immunosuppressive therapy should be considered. Bowel Obstruction and Perforation: Abdominal pain, bowel obstruction and perforation, in some cases leading to death, were observed in patients receiving Rituxan in combination with chemotherapy for DLBCL. In post-marketing reports, which include both patients with lowgrade or follicular NHL and DLBCL, the mean time to onset of symptoms was 6 days (range 1−77) in patients with documented gastro-intestinal perforation. Complaints of abdominal pain, especially early in the course of treatment, should prompt a thorough diagnostic evaluation and appropriate treatment. Immunogenicity: Patients may develop a human anti-chimeric antibody (HACA) response with rituximab treatment. The clinical significance of this is unclear. Pregnancy: B-cell lymphocytopenia generally lasting less than 6 months can occur in infants exposed to rituximab in utero. Immunization: Response rates may be reduced with non live vaccines. Additional Safety Signals: The following serious adverse events have been reported to occur in patients following completion of rituximab infusions: arthritis, disorders of blood vessels (vasculitis, serum sickness and lupus-like syndrome), eye disorders (uveitis and optic neuritis), lung disorders including pleuritis and scarring of the lung (bronchiolitis obliterans), that may result in fatal outcomes, and fatal cardiac failure. See the rituximab Investigator Brochure for additional details regarding safety experience with rituximab.
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14.2 cyclophosphamide

Refer to the FDA approved package insert for complete product information. 14.2.1 Supply Commercially available as a lyophilized powder for reconstitution, in 100 mg, 200 mg, 500 mg, 1gm, and 2 gm vials. 14.2.2 Storage and preparation Intact vials should be stored at room temperature (not to exceed 30oC). Reconstituted solution is stable up to 6 days if refrigerated (2-8 oC). Discard solution after storage for 24 hours at room temperature. 14.2.3 Administration Cyclophosphamide will be diluted in 100 mL of D5W or 0.9% NaCl and infused over 30 minutes or according to institutional standard. Patients will be instructed to drink an adequate amount of fluids and empty their bladders frequently during cyclophosphamide administration.
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14.2.4 toxicities

Myelosuppression, nausea and vomiting, hemorrhagic cystitis, and alopecia. Cystitis can be largely prevented by maintaining a good state of hydration and good urine flow during and after drug administration using the following. Please refer to the package insert for a complete listing of all toxicities.
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14.2.5 hydration guidelines

All patients should receive 0.9%NS at the following volumes (based on cyclophosphamide dose levels) and rates with half the specified volume given before starting cyclophosphamide administration and half the volume given after completion of the cyclophosphamide administration.  
Cyclophosphamide  
Dosage Levels Fluid Volume and Administration Rate  
1 & 2 1000 mL 0.9%NS @ 300 - 500 mL/h  
Levels 3, 4, & 5 2000 mL 0.9%NS @ 300 - 500 mL/h  
Levels 6 2500 mL 0.9%NS @ 300 - 500 mL/h
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14.3 doxorubicin

Refer to the FDA approved package insert for complete product information. 14.3.1 Supply Commercially available as a lyophilized powder for reconstitution in 10, 20, 50 and 100 mg vials. Also available as a 2 mg/mL solution for injection in 10, 20, 50, and 200mg vials. 14.3.2 Toxicities Myelosuppression, stomatitis, alopecia, nausea and vomiting, and acute and chronic cardiac toxicity, manifested as arrhythmias or a congestive cardiomyopathy, the latter uncommon at total cumulative doses less than 500 mg/m2. The drug causes local necrosis if infiltrated into subcutaneous tissue. Please refer to the package insert for a complete listing of all toxicities.
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14.4 vincristine

Refer to the FDA approved package insert for complete product information. 14.4.1 Supply Commercially available in 1 mg, 2 mg, and 5 mg vial sizes. Each ml contains 1 mg of vincristine, 100 mg mannitol, 1.3 mg methylparaben, and 0.2 mg propylparaben. Drug should be stored at 2º-8 oC and should be protected from light.  
14.4.2 Toxicities Peripheral neuropathy, autonomic neuropathy, and alopecia. Local necrosis if injected subcutaneously. Please refer to the package insert for a complete listing of all toxicities.
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14.5 etoposide

Refer to the FDA approved package insert for complete product information. 14.5.1 Supply Commercially available as a 20 mg/mL solution for injection in 5, 25, and 50 mL vials. Each ml contains, 2 mg citric acid, 30 mg benzyl alcohol, 80 mg polysorbate 80, 650 mg of polyethylene glycol 300, and 30.5% alcohol. 14.5.2 Toxicities Myelosuppression, nausea, vomiting, anaphylactoid reactions, alopecia, and hypotension if infusion is too rapid. Please refer to the package insert for a complete listing of all toxicities. 14.6 Administration of vincristine/doxorubicin/etoposide Stability studies conducted by the Pharmaceutical Development Service, Pharmacy Department, NIH Clinical Center, have demonstrated that admixtures of vincristine, doxorubicin, and etoposide in 0.9% Sodium Chloride Injection, USP at concentrations, respectively, of 1, 25 and 125 mcg/mL; 1.4, 35 and 175 mcg/mL; 2, 50 and 250 mcg/mL; and 2.8, 70 and 350 mcg/mL are stable for at least 36 hours at room temperature when protected from light. Also admixtures containing vincristine, doxorubicin and etoposide concentrations of 1.6, 40 and 200 mcg/mL are stable for at least 30 hours at 32 degrees C. For this study, etoposide, doxorubicin, and vincristine comprising a daily dose (a 24-hour supply) will be diluted in 0.9%NS. Product containers will be replaced every 24 hours to complete the planned duration of infusional treatment. Product volumes will be determined by the amount of etoposide present in a 24-hour supply of medication. For daily etoposide doses ≤130 mg, admixtures will be diluted in approximately 500 mL 0.9%NS. For daily etoposide doses >130 mg, admixtures will be diluted in approximately 1000 mL 0.9%NS.  
Etoposide + doxorubicin + vincristine admixtures will be administered by continuous IV infusion over 96 hours with a suitable rate controller pump via a central venous access device.  
For NIH Clinical Center Only: Please see **APPENDIX A** for further details.  
Each participating site is encouraged to mix the vincristine, doxorubicin and etoposide in one bag. If that is not feasible due to institutional constraints, then a site should prepare the continuous infusion of vincristine, doxorubicin and etoposide according to institutional procedures.
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14.7 prednisone

Refer to the FDA approved package insert for complete product information. 14.7.1 Supply Commercially available in a large number of oral dosage strengths including pills and liquid formulations. Tablets should be stored in well-closed containers at temperatures between 1530oC.  
- **Doses**: Prednisone utilization may be simplified by using only 20- and 50-mg tablets to produce individual doses and by stratifying prednisone doses by a patient's body surface area (BSA), according to the chart below. These are recommendations and not requirements.  
BSA (m2) Each Dose 1.25 - 1.49 80 mg 1.5 - 1.83 100 mg 1.84 - 2.16 120 mg 2.17 - 2.41 140 mg 2.42 - 2.6 150 mg 2.61 - 2.69 160 mg 2.7 - 3 170 mg Proximal muscle weakness, glucose intolerance, thinning of skin, redistribution of body fat, Cushingoid facies, immunosuppression, and propensity to gastrointestinal ulceration. Please refer to the package insert for a complete listing of all toxicities.
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14.8 filgrastim

Refer to the FDA approved package insert for complete product information.
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14.8.1 supply

Commercially available in single use vials containing 480 mcg/vial (300 mcg/ml, 1.6 mlvial). Should be stored at 2º-8 oC (do not freeze and do not shake) and is stable for at least 1 year at this temperature. Filgrastim will be given by subcutaneous injection; patient or other caregiver will be instructed on proper injection technique.
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14.8.2 toxicities

Rare anaphylactic reactions with the first dose; bone pain at sites of active marrow with continued administration. Local reactions at injection sites. Constitutional symptoms, increased alkaline phosphatase, LDH, uric acid; worsening of pre-existing inflammatory conditions. Please refer to the package insert for a complete listing of all toxicities.
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14.9 pegfilgrastim

Refer to the FDA approved package insert for complete product information. 14.9.1 Supply Commercially available in a prefilled single use syringe containing 6 mg pegfilgrastim, supplied with a 27-gauge, 1/2-inch needle with an UltraSafe® The needle cover of the prefilled syringe contains dry natural rubber (a derivative of latex). Should be stored at 2° to 8°C (36° to 46°F) in the carton to protected from light. Do not shake. Discard syringes stored at room temperature for more than 48 hours. Avoid freezing; if frozen, thaw in the refrigerator before administration. Discard syringe if frozen more than once. 14.9.2 Toxicities The most common adverse reactions are bone pain and pain in extremity. Please refer to the package insert for a complete listing of all toxicities.
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14.10methotrexate

Refer to the FDA approved package insert for complete product information 14.10.1Supply Commercially available folic acid antagonist, and only the preservative-free preparation may be used for intrathecal injection.
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14.10.2storage

It should be stored at 15-30C and protected from light. Prior to intrathecal or intraventricular injection, the prescribed dose of methotrexate should be reconstituted/diluted with preservativefree 0.9% sodium chloride to a total volume of 3 to 5 mL. Prepared methotrexate doses should be utilized within 4 hours of preparation.
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14.10.3toxicities

It can cause leukopenia, and as such leucovorin may be administered 24 hours after each dose. It can cause headaches, drowsiness, and blurred vision. It can also cause a transient acute neurologic syndrome manifested by confusion, hemiparesis, seizures, and coma. Please refer to the package insert for a complete listing of all toxicities.
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14.11 cytarabine

Refer to the FDA approved package insert for complete product information 14.11.1Supply A commercially available pyrimidine nucleoside antimetabolite.
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14.11.2storage

Cytarabine should be stored at –15-30C, and used within 2 years of the date of manufacture.  
Prior to intrathecal injection it is reconstituted with preservative free 0.9% sodium chloride, and should be utilized within 4 hours of preparation. Prior to intrathecal or intraventricular injection, the prescribed dose of cytarabine should be reconstituted/diluted with preservative-free 0.9% sodium chloride to a total volume of 3 to 5 mL.
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14.11.3toxicities

It can cause myelosuppression, fever, dizziness, somnolence, and arachnoiditis. Please refer to the package insert for a complete listing of all toxicities.
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(dox) and etoposide (etop) during treatment of aggressive B-cell lymphomas indicate doses need not be routinely reduced for hepatic dysfunction. Proc Am Soc Clin Oncol, 2005. 24.  
22. Juweid, M.E., et al., Response assessment of aggressive non-Hodgkin's *lymphoma by* integrated International Workshop Criteria and fluorine-18-fluorodeoxyglucose positron emission tomography. J Clin Oncol, 2005. 23(21): p. 4652-61.  
23. Kostakoglu, L., et al., PET Predicts Prognosis After 1 Cycle of Chemotherapy in Aggressive Lymphoma and Hodgkin's Disease. J Nucl Med, 2002. 43(8): p. 1018-1027.  
24. Gallamini, A., et al., *The predictive value of positron emission tomography scanning* performed after two courses of standard therapy on treatment outcome in advanced stage Hodgkin's *disease.* Haematologica, 2006. 91(4): p. 475-81.  
25. Yusuf, S., et al., Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med, 1992. 327(10): p. 685-691.  
26. Hummel, M., et al., *A Biologic Definition of Burkitt's Lymphoma from Transcriptional* and Genomic Profiling. N Engl J Med, 2006. 354(23): p. 2419-2430.  
27. Magloire, L.K., et al., *Burkitt's lymphoma of the ovary in pregnancy.* Obstet Gynecol, 2006. 108(3 Pt 2): p. 743-5.
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16 appendix a epoch admixtures

Preparation All 3-in-1 admixtures dispensed from the Pharmacy will contain a 24-hour supply of etoposide, doxorubicin, and vincristine, PLUS 40 mL overfill (excess) fluid and a proportional amount of drug to compensate for volume lost in parenteral product containers and administration set tubing.  
| Total Volume in the  Product (including overfill)   |                                    |       |         |
|-----------------------------------------------------|------------------------------------|-------|---------|
| < 130 mg                                            | 528 mL                             | 40 mL | 568 mL  |
| > 130 mg                                            | 1056 mL                            | 40 mL | 1096 mL |
| Volume of Fluid  Containing a Daily  Dose           | Volume of  Overfill (fluid + drug) |       |         |
| Etoposide  Dose                                     |                                    |       |         |  
Before dispensing 3-in-1 admixtures, Pharmacy staff will:
[1] Purge all air from the drug product container, [2] Attach an administration set appropriate for use with a portable pump, [3] The set will be primed close to its distal tip, and [4] The set will be capped with a Luer-locking cap.  
Pre-printed product labeling will identify the 'Total Volume To Infuse' and the 'Volume of Overfill (fluid + drug)'. Bags will be exchanged daily for four consecutive days to complete a 96-hour drug infusion (unless treatment is interrupted or discontinued due to un-anticipated events).
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administration

Portable pumps used to administer etoposide + doxorubicin + vincristine admixtures will be programmed to deliver one of two fixed volumes at one of two corresponding fixed rates based on the amount of etoposide and fluid that is ordered (see the table, below).  
| Volume of Overfill (drug-containing   | Administration Rate   |       |            |
|---------------------------------------|-----------------------|-------|------------|
| fluid)*                               |                       |       |            |
| Etoposide                             | Total Volume to       |       |            |
| Dose                                  | Infuse per 24 hours   |       |            |
| < 130 mg                              | 528 mL                | 40 mL | 22 mL/hour |
| > 130 mg                              | 1056 mL               | 40 mL | 44 mL/hour |  
* DO NOT attempt to infuse the overfill.  
  
At the end of an infusion, some residual fluid is expected because overfill (excess fluid and drug) was added; however, nurses are asked to return to the Pharmacy for measurement any drug containers that appear to contain a greater amount of residual drug than expected. Example at right: The amount of fluid remaining in a bag after completing a 24-hour infusion (1056 mL delivered).
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17 appendix b performance status

| ECOG Performance Status Scale                                                                                                                                                              | Karnofsky Performance Scale                                        |                                                            |             |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------|------------------------------------------------------------|-------------|
| Grade                                                                                                                                                                                      | Descriptions                                                       | Percent                                                    | Description |
| 100                                                                                                                                                                                        | Normal, no complaints, no  evidence of disease.                    |                                                            |             |
| Normal activity. Fully active,                                                                                                                                                             |                                                                    |                                                            |             |
| 0                                                                                                                                                                                          | able to carry on all pre-disease  performance without restriction. | Able to carry on normal activity;                          |             |
| 90                                                                                                                                                                                         | minor signs or symptoms of  disease.                               |                                                            |             |
| Symptoms, but ambulatory.  Restricted in physically strenuous  activity, but ambulatory and able  to carry out work of a light or  sedentary nature (e.g., light  housework, office work). | Normal activity with effort;                                       |                                                            |             |
| 80                                                                                                                                                                                         | some signs or symptoms of  disease.                                |                                                            |             |
| 1                                                                                                                                                                                          | Cares for self, unable to carry on                                 |                                                            |             |
| 70                                                                                                                                                                                         | normal activity or to do active  work.                             |                                                            |             |
| In bed <50% of the time.  Ambulatory and capable of all  self-care, but unable to carry out  any work activities. Up and  about more than 50% of waking  hours.                            | Requires occasional assistance,                                    |                                                            |             |
| 60                                                                                                                                                                                         | but is able to care for most of  his/her needs.                    |                                                            |             |
| 2                                                                                                                                                                                          | Requires considerable assistance                                   |                                                            |             |
| 50                                                                                                                                                                                         | and frequent medical care.                                         |                                                            |             |
| 40                                                                                                                                                                                         | Disabled, requires special care  and assistance.                   |                                                            |             |
| In bed >50% of the time.  Capable of only limited self-care,  confined to bed or chair more  than 50% of waking hours.                                                                     |                                                                    |                                                            |             |
| 3                                                                                                                                                                                          | Severely disabled,                                                 |                                                            |             |
| 30                                                                                                                                                                                         | hospitalization indicated. Death  not imminent.                    |                                                            |             |
| 100% bedridden. Completely  disabled. Cannot carry on any  self-care. Totally confined to bed  or chair.                                                                                   | 20                                                                 | Very sick, hospitalization  indicated. Death not imminent. |             |
| 4                                                                                                                                                                                          | 10                                                                 | Moribund, fatal processes  progressing rapidly.            |             |
| 5                                                                                                                                                                                          | Dead.                                                              | 0                                                          | Dead.       |  
18 APPENDIX C: NIH IRB form for participating sites Reporting of Deviations Noncompliance **and Unanticipated problems**  
| NIH PROBLEM REPORT FORM                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |                                                                                                                                                                                                                                                                            |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| NCI Protocol #: 10-C-0052_9177                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Protocol Title: Phase II Study of Dose-Adjusted  Epoch+/- Rituximab in Adults with Untreated Burkitt  Lymphoma, C-Myc Positive Diffuse Large B-Cell  Lymphoma and Plasmablastic Lymphoma Report version: (select one) ____Initial Report  ____Revised Report ____Follow-up |
| Site Principal Investigator: Date of problem:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | Location of problem: (e.g., patient's home, doctor's  office )                                                                                                                                                                                                             |
| Who identified the problem? (provide role (not name of person): nurse, investigator, monitor,  etc…) Brief Description of Subject (if  applicable) (Do NOT include personal  identifiers) Sex: ___ Male ___ Female Age:  ___ Not applicable (more than subject is involved) Diagnosis under study:  Name the problem: (select all that apply)  [ ] Adverse drug reaction  [ ] Abnormal lab value  [ ] Death  [ ] Cardiac Arrest/ code  [ ] Anaphylaxis  [ ] Sepsis/Infection  [ ] Blood product reaction [ ] Unanticipated surgery/procedure  [ ] Change in status (e.g. increased level of care required)  [ ] Allergy (non-medication)  [ ] Fall  [ ] Injury/Accident (not fall)  [ ] Specimen collection issue  [ ] Informed consent issue |                                                                                                                                                                                                                                                                            |  
[ ] Ineligible for enrollment [ ] Breach of PII [ ] Tests/procedures not performed on schedule
[ ] Other, brief 1-2 word description: _________________________
Detailed Description of the problem: (Include any relevant treatment, outcomes or pertinent history):
*Is this problem unexpected? *(see the definition of unexpected in the protocol))* __YES __NO
Please explain:
*Is this problem related or possibly related to participation in the research? __YES __NO
Please explain: *Does the problem suggest the research places subjects or others at a greater risk of harm than was previously known or recognized? __YES __NO Please explain:
Is this problem? (*select all that apply*)
[ ] An Unanticipated Problem* that is: [ ] Serious [ ] Not Serious [ ] A Protocol Deviation that is: [ ] Serious [ ] Not Serious [ ] Non-compliance *Note if the 3 criteria starred above are answered, "YES", then this event is also a UP.  
Is the problem also *(select one)* [ ] AE [ ] Non-AE Have similar problems occurred on this protocol **at your site?** __YES __NO If "Yes", how many? ____ **Please describe:**
Describe what steps you have already taken as a result of this problem:
In addition to the NIH **IRB, this problem is also being reported to:** (*select all that apply*)
[ ] Local IRB [ ] Study Sponsor [ ] Manufacturer : ____________________ [ ] Institutional Biosafety Committee [ ] Data Safety Monitoring Board [ ] Other: ____________________________________ [ ] None of the above, not applicable INVESTIGATOR'S SIGNATURE: DATE:
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19 appendix d tumor biopsy

9177 Tumor Biopsy Specimen Submission Form  
| 9177 Patient ID: _______________ Date form submitted: ___/__/____  Patient Initials: ___________ Participating Group Study No.: ___________ Patient Hospital No: _________ Participating Group Patient ID: ___________  Institution/Affiliate: ______________________   |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
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to be completed by submitting

Does specimen accompany this form? (NOTE: Core needle biopsy specimens for each patient should be submitted with this form. If specimens will not be submitted, specify the reason and submit the form as required by protocol.) No, specify reason: _______________________________ Institution error: ____ Sample lost or destroyed: ____ Other, specify: __________ Yes: Date specimen collected: ____/____/______ Number of core needle biopsy specimens sent with this form: ________ Sample period: Pre-treatment: Y:____ N: ____  
| Submitted by: ______________________ Phone number: ____________________  Institution/Affiliate: ________________ NCI institution code: ________________   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------|
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to be completed by receiving

Date Specimen received: ________________ Specimen ID number: _________________ Specimen condition (Mark one with an X)  
| _____Usable                                                       | ____ No specimen received   | _____ Insufficient amount   |
|-------------------------------------------------------------------|-----------------------------|-----------------------------|
| _____ Damaged or unusable                                         | _____Thawed                 | ____ Clotted                |
| Received by: __________________ Phone number: ___________________ |                             |                             |
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20 appendix e roster of

NOTE: Effective with Amendment M, the Roster of NCTN Sites has been removed from the protocol document. This information will be reported within the NIH IRB application. Participating sites may find this information on the CTSU and ClinicalTrial.gov websites.
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21 appendix f burkitt lymphoma

FOUNDATION FOR BURKITT LYMPHOMA RESEARCH
BURKITT LYMPHOMA GENOME SEQUENCING PROJECT (BLGSP) 04/17/13
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executive summary

The Foundation for Burkitt Lymphoma Research (FFBLR) has established a collaborative effort with the National Cancer Institute (NCI), in order to develop a genomic databank for Burkitt Lymphoma (BL). The BLGSP will compile genetic changes present in BL tumors, analyze the data to identify diagnostic, prognostic, or therapeutic markers or targets, and publish the results. As with other cancer sequencing projects, the goal is to identify potential genetic changes in patients with BL that could lead to better prevention, detection and treatment of the cancer. The effort will be coordinated through the Foundation for the National Institutes of Health (FNIH). The NCI, through the Office of Cancer Genomics (OCG), will provide the administrative, physical and analytical infrastructure in order to carry out this project. This will enable the FFBLR to utilize existing Standard Operating Procedures (SOPs) developed by OCG, as well as relationships OCG has established with other organizations, in order to carry out this project. This effort will enhance the scientific integrity and credibility of the BLGSP, and be consistent with the conduct and methodologies used in other NCI sponsored cancer sequencing projects. The FFBLR will assist in the accrual of the tissues by identifying sites in the US, Europe and Africa, making the initial contacts and providing administrative support. NCI will establish the contracts and protocols for accrual and quality control that are already in place as part of ongoing projects, such as the Cancer Genomic Characterization Initiative (http://cgap.nci.nih.gov/cgci.html). The FFBLR will participate in the scientific leadership of the BLGSP, including having members of its Scientific Advisory Board review the data from the project; provide the biologic context for publication and dissemination within the appropriate scientific communities. It is anticipated that the project timeline will be 3-4 years; approximately 2 years to identify and collect appropriate tissue and data from approximately 120 qualifying patients with BL (Phase I),
about 6-12 months to complete the sequencing and analysis (Phase II), 6 months for validation studies (Phase III), and another 3-6 months to publish the data (Phase IV).
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introduction

Dr. Jean Paul Martin and Dr. Marie Reine Martin have established a Foundation for Burkitt Lymphoma (BL) Research in Geneva, Switzerland to further the understanding and the treatment of BL.  They made this decision because their son Xavier was diagnosed in July 2009 with BL and passed away from a relapse of the disease in May 2010.  
Burkitt Lymphoma, first described by Dr. Denis Parsons Burkitt in 1956, is an uncommon type of Non-Hodgkin Lymphoma, often but not exclusively affecting children.  It is a highly aggressive type of B-cell lymphoma and often involves body parts other than lymph nodes.  The disease is associated with a chromosomal translocation of the MYC gene.  The tumor consists of sheets of a monotonous (similar in size and morphology) population of medium size lymphoid cells with high proliferative activity and apoptotic activity described as a "starry sky" appearance under low power magnification.  
Currently BL is divided into three main clinical variants:  1.  Endemic: This BL variant occurs mainly in equatorial Africa, where the disease was first described and is the most common malignancy in children. In 95% of cases, the children are infected with Epstein-Barr virus, which is presumably key to its etiology.  The disease involves children much more than adults.  The disease characteristically involves the jaw or other facial bone, and may involve the distal ileum, cecum, ovaries, kidney or the breast.  2.  Sporadic: This BL variant is found outside of Africa and is usually not associated with Epstein-Barr virus infection, but has morphological and molecular features in common with endemic BL.  The jaw is less commonly involved, whereas the ileo-cecal region is the most common site of involvement.  3.  Immunodeficiency-associated:
This variant is usually associated with HIV infection and can be associated with the initial manifestations of AIDS, but can also occur in post-transplant patients who are taking immunosuppressive drugs. Current chemotherapy regimens are effective in approximately 40-90% of patients depending on age, stage of the disease, treatment regimen, and site of the treatment facility. Hence, new treatments are needed to improve the efficacy of current regiments and potentially to substitute less toxic agents for the high intensity chemotherapeutic drugs that are currently given. With this as a brief background of BL, the vision of the Foundation is to provide monetary support of prioritized, key pre-clinical and clinical research activities that will provide a better understanding of the mechanisms of the disease and lead to more effective treatment algorithms. The Foundation has a renowned international Advisory Board including Professor Jane Apperley, Professor Riccardo Dalla-Favera, Professor Gerard Evan, Dr. Stephen Friend, Professor John Gribben, Dr. Ariela Noy, and Dr. Louis Staudt. The Executive Director of the Foundation is Dr. John D. Irvin. The Foundation's first key research project is to establish a comprehensive databank of genomic and clinical data in patients with BL. The purpose of this document is to outline and describe the activities associated with developing the database.
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aim

This project will establish a comprehensive databank of genomic sequence from patients with BL, utilizing tumor DNA and matched normal DNA as well as tumor RNA. Clinical data will also be collected so that associations between clinical parameters and genetic abnormalities can be discovered.
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significance

Since the discovery in 1983 of MYC translocations in BL, little progress has been made in understanding the molecular pathogenesis of the disease. MYC, the defining oncogene for this cancer, is itself insufficient to transform primary cells and actually induces apoptosis unless growth factors are provided or cooperating oncogenes are activated. Loss of p53 function by mutation or by inactivation of INK4aARF may contribute to cell survival in a fraction of cases.  
However, there has yet to be a comprehensive effort to discover new genetic aberrations associated with BL using high throughput methods. There are several major unmet needs in the clinical management of BL that require urgent attention. First, current chemotherapy is ineffective in roughly 20% of cases, and is associated with therapy induced toxicity and death. Because of the toxicity, patients with BL over the age of 70 are ineligible for this potentially curative therapy. Second, young individuals exposed to these intensive regimens face the real possibility of secondary malignancies years later. Finally, children with endemic BL in Africa in general do not receive these curative chemotherapy regimens because of the lack of hospital support for the management of post-treatment infections, and consequently most will die of their disease. What is needed, therefore, are new approaches to the therapy of BL that are based on an understanding of its molecular pathogenesis and the regulatory pathways that it utilizes for proliferation and survival. Currently, we have no insight into the possible involvement of kinases and signaling pathways that might promote the high rate of proliferation that characterizes these tumors. Likewise, mechanisms that prevent apoptosis of BL cells, besides p53 inactivation, have yet to be discovered. Burkitt Lymphoma is derived from the germinal center stage of B cell differentiation, and as such expresses a professional mutator, activation-induced cytosine deaminase (AID). AID is likely involved in generating the breakpoints that lead to MYC translocations in sporadic BL and almost certainly targets many cellular genes for mutation. Hence, BL may utilize AID-generated mutations to modulate oncogene and tumor suppressor pathways. This BL comprehensive genome characterization project will shed considerable light on the oncogenic capacity of AID and identify other potential disease-causing candidates. An additional fascinating question is whether genetic alterations in the BL genome may influence the symbiotic relationship with the Epstein-Barr virus in the endemic variant in a proportion of the sporadic and immunodeficiency-related cases. EBV viral proteins can mimic Notch signaling (EBNA2), CD40 signaling (LMP1), and B cell receptor signaling (LMP2). It may be necessary for the BLs to acquire mutations in these pathways to shape the cellular response to these virally derived signals. Many key clinical questions may be illuminated by knowledge of genomic abnormalities in BL. Why do approximately 10-60% of patients treated with potentially curative chemotherapy nonetheless succumb to their disease? How do the genomic alterations in the BL variants (endemic, sporadic, immunodeficiency-related) differ, and how do these differences affect their response to therapy? What new therapeutic options may be available to augment or supplant high-dose chemotherapy?
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study population

The study population should include fresh tissue samples (case-matched tumor and normal) from 60 adult patients with sporadic BL; and tissue from approximately 20 patients of each of the other three variants, pediatric sporadic, endemic and HIV-associated BL. It is anticipated that about double that number of cases will need to be collected as there is about a 50% failure rate at the pathology and molecular processing stages.
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study conduct and standard operating

In order to enhance the scientific integrity and credibility of the Burkitt Lymphoma Genome Sequencing Project (BLGSP), the project will be carried out utilizing SOPs developed by the OCG at the NCI. The BLGSP-specific SOPs can be found in the OCG Tumor Molecular Characterization Projects Standard Operating Procedures manual (http://cgap.nci.nih.gov/files/OCG_SOP_Manual.pdf) and are consistent with those currently utilized in the NCI-sponsored HIV+ Tumor Molecular Characterization Project (HTMCP). Using the SOPs, the tissues will be accrued by collaborators (referred to as Tissue Source Sites [TSS]) with access to BL patients. Each TSS will need to obtain an institutional review board (IRB)-approved study protocol that allows for collection of human tumor tissue and matched normal tissue (preferably blood). Upon approval, all TSS will be required to collect and store the tissues, perform site-capable pathology analysis to determine the BL diagnosis, and provide the BLGSP-required clinical data. The above-referenced OCG Tumor Molecular Characterization Projects SOP Manual includes templates of an informed consent and an institutional certification letter, which can be adapted by each TSS for their use. Every patient studied in the BLGSP must be enrolled in a site-specific protocol, and agree to participate by signing an informed consent. The institutional certification letter states that the IRB understands that the data generated will be made publicly available with the appropriate patient protection procedures (http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/about.html).
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tissue collection and preparation

Procedures for tissue collection, preparation, pathology review and shipment in the BLGSP are detailed in the OCG Tumor Molecular Characterization SOP Manual. Adherence to the SOPs is essential to ensure that the quality of the tissues collected meet the technical requirements of the methods of analysis. The protocols include information on tissue collection and preservation by freezing, pathology review, collection of blood samples for molecular characterization, shipping cryoports containing frozen biosamples for processing and extraction of nucleic acids, sample shipping guidelines, sample identifier standards, and disposition form for remaining macromolecules/tissues that are contributed to the project. Templates for suggested language for prospective tissue collection and the data release policy are also included within the SOPs.
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tissue requirements

Following is a summary of the tissue requirements for the BLGSP. The specific detailed requirements are included in the above referenced SOPs.  
- Paired tumor and matched normal (non-involved tissue or blood) of untreated cases must be available in sufficient quantities.  
- If blood is the normal tissue, documentation of normal peripheral white blood cell counts and smears must be provided since in rare instances, BL cells can be in the peripheral blood. There are 2 ways of getting normal tissue without tumors: a) Granulocytes can be separated from lymphocytes with Ficoll. b) Also with Ficoll separation, flow cytometry analysis can be performed with CD10, a BL surface marker.  
- Pre-treatment blood sample is preferred as the source of normal tissue. However, if a tumor specimen is pre-existing and the patient is alive and can be re-consented following treatment for the collection of a post-treatment blood sample, then that will be acceptable.  
- Tissues (both normal and tumor) need to be snap frozen. Currently the project anticipates that ~100 mg of tumor tissue and 10 ml of blood is required, but this may change as the sequencing characterization technology improves.  
- A portion of tumor adjacent to the snap frozen sample will be assessed to estimate %
tumor cells, with additional immunohistochemical (IHC) stains and FISH to be performed to validate the diagnosis, as needed (see below). Tumors need to have minimum 70-80% tumor nuclei as assessed on the H&E section from the frozen tissue with ~80% viable cells.  
- Standard World Health Organization diagnostic criteria for BL must be fulfilled.  
Specifically, the tumor cells have the "starry-sky" appearance, be positive for CD10 and/or BCL6 by IHC and >90% of the cells need be Ki67 positive. It would be optimal if the presence of MYC to immunoglobulin locus translocation was confirmed by fluorescent in situ hybridization (FISH). At least 12 paraffin-embedded slides, or even better a block, have to be provided, from each case for pathology review by the project pathologists.  
- Clinical data (see SOPs) has to be collected at the time of diagnosis, updated after treatment, and then every year for the next 2 years If tumor tissue or blood/constitutional tissue is not available, but clinical information and paraffin-embedded slides or block(s) are, we would consider accepting nucleic acids from pathology review-confirmed cases that meet the following criteria:
- At least 10 µg of RNA with RNA Integrity Number (RIN) > 7 as determined on an Agilent Bioanalyzer or similar system
- At least 20 µg each of tumor and normal high molecular weight (>80% of the molecules are >10 kb) DNA
The tissues will be processed in a single biospecimen-processing center using standard protocols developed for and validated in Therapeutically Applicable Research to Generate Effective Treatments (TARGET) and The Cancer Genome Atlas (TCGA). The RNA and DNA will be quality controlled and the match of the tumor and normal DNA confirmed. As part of the processing, the DNA will be whole genome amplified by the method considered the most optimal for genomic characterization at the time when this project will be ready to do so. One of the BLGSP's outcomes will be the availability of the DNA and/or RNA for other projects.
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pathology review/verification

The review of all tissues by a central pathology review panel of three board-certified hematology pathologists will ensure that the samples that are molecularly characterized are BL, and remove the subjectivity encountered in standard pathology practice. The pathology criteria for BL diagnosis include: 1) characteristic histological appearance; 2) Ki67 immunohistochemical staining in >90% of tumor nuclei; 3) CD10+ and/or BCL6+ by immunohistochemistry; 4)
MYC/Ig translocation by FISH analysis; BCL2 staining by IHC and those cases which are positive, will by analyzed by *MYC/BCL2* FISH. A SOP for this review and verification has been established and is available in the BLGSP section of the OCG SOP manual.
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sequencing analysis and validation

One of the major objectives of the BLGSP will be to generate genomic-scale DNA and/or RNA sequence from case-matched tumor-normal pairs from patients with BL. For DNA as well as RNA sequencing, normal DNA needs to be sequenced to define which novel sequence variants are germline and which are somatic changes. The plan is to initiate sequencing once a critical number of cases (12-20) have been collected and continue sequencing in batches throughout the term of this project. We anticipate that the cost of whole genome sequence will be decreasing, though the exact cost cannot be estimated. The analysis of the genomic DNA sequence will provide information of single-nucleotide polymorphisms (SNPs) for loss of heterozygosity, somatic mutations, genomic rearrangements and copy number. We anticipate that sufficient funds will be available for whole transcriptome sequencing (mRNA-seq and miRNA-seq). The analysis of that data results in digital gene expression profile, identification of alternative spliced variants, discovery of fusion transcripts created by genomic rearrangements, RNA editing (in comparison with the genomic sequence), confirmation of mutation calls, and if mutant or wild type alleles are expressed as mRNA (either due to loss of heterozygosity or imprinting).  
While the cost and quality of sequencing (2nd, 3rd generation) in two years is impossible to predict (currently the costs are decreasing rapidly and the quality of the sequence is improving as well), there is every reason to anticipate that it will be the norm to sequence the genome more than the current 30X (50-100X?) and include the transcriptome as well. The current proposal does not include epigenetic characterization, however whatever materials will be left over could be used in the future to do genome-wide characterization of the methylation profile. The NCI project team will develop an analytical protocol for the data generated, including:  
- Analysis of the copy number alternations with integration with digital gene expression
- Identification of somatic mutations
- Identification of translocations
Taken together, these analyses will look for recurrent lesions within BL as a whole and within the BL variants. Genetic changes will be placed into biological pathways and integrated using available methods. The findings will be validated in a new population cohort via highthroughput evaluation of gene alterations in BL as a whole and within the BL variants. The validation cohort will include up to 200 patients; the proportion of subtype cases will be selected based on the results obtained in the discovery phase (II). Validation studies performed in this new cohort will allow for mutations uncovered in Phase II to be verified as true and increase the power to estimate the frequency with which they occur. Moreover, validation will enable evaluation of the clinical relevancy of the genetic changes found.
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governance

The tissue contributors will be co-authors on the first manuscript and may collaborate in the future in others. The project will have a steering committee (SC) whose membership includes members of the FFBLR's scientific advisory board (Dr. Louis Staudt, Professor Riccardo DallaFavera, Dr. Stephen Friend, Dr. Ariela Noy, and Dr. John Irvin, Executive Director FFBLR), one representative each from the contractor(s) doing the sequencing and tissue processing, the members of the pathology review board and 1-2 representatives from OCG as needed. During the first 2 years of the project, the SC will meet by teleconference quarterly, and face-to-face annually to assess the progress in tissue accrual and any issues, which may arise in the process to isolation of the molecular analytes. The sequencing will be performed by contractors, which will be put in place by OCG. Once sequencing starts, the SC needs to meet monthly through teleconferencing and face to face every 6 months.
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data release policy and publication

The data that are generated will be submitted to publicly accessible databases developed for HTMCP and other projects. The NCI database is called the Data Coordinating Center and it allows an easy access to all data generated (TARGET, CGCI and TCGA) as well as analytical tools developed for other large-scale sequencing projects. The BLGSP will be listed on the CGCI web page and the Foundation acknowledged as a collaborator. The procedures developed for the other projects include submission of the sequence generated to publicly accessible databases (currently called sequence-read archive), which are an NCI-defined resource used by all NCI projects. The BLGSP agrees to abide by the data release policy formulated for the HTMCP (**http**://cgap.nci.nih.gov/files/H_TMCP_Data_Release_Policy.pdf). Every effort will be made to rapidly, and not later than in 3-6 months after validation, publish the first manuscript describing the data and including a high-level analysis.