CALGB C10001 - "A Phase II Trial of Sequential Chemotherapy, Imatinib Mesylate (Gleevec, STI571), and Transplantation for Adults With Newly Diagnosed Ph+ Acute Lymphoblastic Leukemia"

NOTES:  Only St. Luke's Hospital is currently approved for BMT.

                QARC approval required for TBI.

Treatment Plan    (Supplied Drug:  Imatinib Mesylate)

Course I - Remission Induction

Must begin Course II w/i 2 wks of ANC >1000/µl and platelets >100,000/µl.  CALGB pts should have perip blood & BM submitted for CALGB 8461 & 9665 (if also enrolled on a CALGB tx protocol for previously untreated ALL) and CALGB 9862 at time of enrollment on CALGB C10001.  SWOG pts must have perip blood & BM submitted for SWOG 9007 at time of enrollment on CALGB C10001.

Course II

Imatinib Mesylate (Gleevec):  400mg, PO, BID, Days 1-28

BM asp & bx on Day II-29 to assess response.  If marrow M0 or M1, pts may continue protocol therapy.  Submit BM asp & bx for CALGB 9862 on Day II-29.

Course III - CNS Prophylaxis

Begin w/i 1 wk of BM exam on Day II-29.

NOTE:  Recommended that IV Vincristine be administered prior to initiation of IV Methotrexate.  IT Methotrexate should be administered later in day (any time during IV Methotrexate.

Lumbar Puncture:  For CSF exam for leukemia required on Days 1, 8, & 15.  Perform anytime during 3-hr IV Methotrexate on these days, but recommended to be done at end of 3-hr IV Methotrexate infusion.

IT Methotrexate:  15mg total, IT, once weekly, x 3 wks (Days 1, 8, & 15) + 50mg Hydrocortisone

Vincristine:  2mg total, IV, once weekly, x 3 wks (Days 1, 8, & 15)

IV Methotrexate:  1000mg/m², IV over 3 hrs (in 1 liter D5W or NS), Days 1, 8, & 15.  Prior to beginning IV-Mtx, pts should be pre-hydrated w/500-1000mL D5W or NS plus 100 mEq/L of sodium bicarb.  Continue hydration & maintain urine pH>6.  Strongly recommended that addit hydration (w/D5W or NS plus 100 mEq/L of sodium bicarb) be given on Days III-2, III-9, & III-16 when pt returns for IV Leucovorin.

PO Methotrexate:  25mg/m², PO, q6hrs, x 4 doses (total), beginning 6 hrs after starting IV-Mtx (Days 1 & 2, 8 & 9, 15 & 16).  Dose of PO-Mtx will be adjusted to maintain serum Mtx level between 1-2µM.

Serum Mtx Levels:  Days 2, 4, 9, 11, 16, & 18

IV Leucovorin:  25mg/m², IV push, 6 hrs after 4th (last) PO-Mtx dose (i.e., 30 hrs after starting IV-Mtx)

PO Leucovorin:  5mg/m², PO, q6hrs, x 8 doses &/or serum Mtx level <0.05µM (begin 12hrs after IV-Lcv)

Cotrimoxazole DS:  1 tab, PO, BID, 3 days/wk (for PCP prophylaxis until chemo completion) or inhaled aerosolized pentamidine (300mg, 1x/mo) if allergic to sulfonamides.  Do not give Cotrimoxazole on same day as Mtx, but can be given later in same wk.

Bone Marrow Asp & Bx/Perip Blood:  BM asp/bx on Day III-29.  Perip blood & BM specimens for CALGB 9862 (mandatory) on Day III-29.

Course IV

No upper limit for time to recovery from cytopenia.  Course IV should ideally start on or shortly after Day III-29.

Imatinib Mesylate (Gleevec):  400mg, PO, BID, Days 1-28

BM asp & bx on Day IV-29 to assess response.  If marrow M0 or M1, pts may continue protocol therapy.  Submit BM asp & bx for CALGB 9862 on Day IV-29.

Course V (transplants must be done at CALGB- or SWOG-approved transplant center)

(A):  Allogeneic Transplant for Pts w/HLA-Matched Sibling Donor

May begin >72 hrs & <10 days after last dose of Gleevec in Course IV.  All pts will have BM exam & RT-PCR assay (submit samples through CALGB 9862) on Day 30 post-transplant following Course V.

Allopurinol:  300mg, QD, Days -8 through -2 (start day prior to RT)

Fractionated Total Body RT:  Days -7 through -4 (1320cGy/11fx/120cGy each) over 4 days.  3fx/day will be given on Days -7 through -5 and 2fx/day on Day -4.  Separate each fx by >4 hrs.  Males will receive 400cGy boost to testes.

Donor:  Will receive G-CSF at 16µg/kg/day, SQ, starting 2 days pre-planned apheresis.  Starting Day 3 of mobilization, apheresis & cell collection will proceed daily until minimum of 5 x 10⁶ CD34+ cells/kg (recipient wt) are collected or to total of 5 aphereses.

VP-16:  60mg/kg (corrected body wt), IV over 4 hrs, Day -3

Tacrolimus:  0.05mg/kg/day, CI, Days -1 through +3.  Give 0.03mg/kg/day, CI, Days +4 through +14.  Give 0.03mg/kg/day, CI, Days +14 through +56 or in divided doses q12hrs or PO formulation (when tolerated) at ratio of 1:4 (IV:PO) in 2 divided doses/day based on last IV dose.

PBSC Transplant:  Day 0

Methotrexate:  10mg/m², IV, Day +1, starting 24hrs after PSC infusion is complete. Give 5mg/m², IV, Days +3 & +6.

G-CSF:  5µg/kg/day, SQ, beginning Day +4 until ANC >1500/µL x 2 consecutive days or >5000/µL x 1 day.

(B):  Autologous Transplantation for Pts Without an HLA-Matched Sibling Donor

Begin >72 hrs & <10 days following last dose of Gleevec in Course IV.  Must have BM exam and RT-PCR assay (CALGB 9862) on Day 30 post-transplant following Course V.

PBSC Mobilization & Leukapheresis

Etoposide:  10mg/kg/day (corrected body wt), CI over 96 hrs, Days 1-4.  Total dose = 40mg/kg.

Ara-C:  2000mg/m², IV over 2 hrs, q 12 hrs x 8 doses, Days 1-4

Prophylaxis:  Antifungal & antibacterial therapy required beginning Day 5

G-CSF:  10µg/kg/day, SQ (total dose) in 1 or 2 injections beginning Day 14.  Continue until PBSC collection completed or WBC >50,000/µL.  Do not skip/reduce for bone pain.

STI571:  400mg, PO, BID (start after stem cell collection is complete until 72 hrs pre-transplant)

Leukapheresis will start when WBC >10,000/µL.  Target is 5 x 10⁶ CD34+ cells/kg.  Send aliquot of each leukapheresis product for RT-PCR assay (via CALGB 9862).

Autologous PBSC Transplantation

Pt must remain in CR documented by normal BM w/<5% blasts w/i 2 wks of transplant and have stable or improving perip blood counts.  ANC >500/µL & platelets >50,000/µL.  PBSC transplant to take place >4 wks following hospital D/C and after recovery from myelosuppression toxicities.  Gleevec must be stopped >72 hrs & <10 days pre-autologous transplant.

Allopurinol:  300mg, PO, QD, Days -9 through -2

Fractionated Total Body RT:  Days -8 through -5 (1320cGy/11fx/120cGy each) over 4 days.  3fx/day will be given on Days -8 through -6 and 2fx/day on Day -5.  Separate each fx by >4 hrs.  Males will receive 400cGy boost to testes.

VP-16:  60mg/kg (corrected body wt), IV over 4 hrs, Day -4

Cyclophosphamide:  100mg/kg (corrected body wt), IV over 2 hrs, Day -2 (hydrate vigorously)

Autologous PBSC Transplant:  Day 0

G-CSF:  5µg/kg/day (actual body wt), SQ, beginning Day 0 until ANC >1500/µL x 2 days or >5000/µL x 1 day.

(C):  No Transplantation for Pts Who are NOT Transplant Candidates

Pts should NOT be removed from study.  Will receive same high-dose Ara-C & VP-16 therapy for stem cell mobilization during autologous transplant, but will not have stem cells collected.  Therapy to begin >72 hrs & <10 days following last dose of Gleevec in Course IV.  Must have BM exam & RT-PCR assay (submit through CALGB 9862) on Day 30 following Course V.

VP-16:  10mg/kg/day (corrected body wt), CI over 96 hrs, Days 1-4 (total dose=40mg/kg)

Ara-C:  2000mg/m2, IV over 2 hrs, q 12 hrs, x 8 doses, Days 1-4

Prophylaxis:  Antifungal & antibacterial therapy beginning Day 5

G-CSF:  10µg/kg/day, SQ (total dose) in 1 or 2 injections beginning Day 14.  Continue until WBC >5000/µL.  Do not skip/reduce for bone pain.

Course VI - Gleevec Maintenance Therapy

• Allogeneic transplant pts:  Gleevec, 400mg, PO, QD, beginning Day 30 post-transplant and continuing until 2 consecutive negative RT-PCR assays 3 mos apart are documented or until relapse.* 

• Autologous transplant pts:  Gleevec, 400mg, PO, BID, beginning Day 30 post-transplant and continuing until 2 consecutive negative RT-PCR assays 3 mos apart are documented or until relapse.*

• "No transplant" pts:  Gleevec, 400mg, PO, BID, beginning Day 30 and continuing until 2 consecutive negative RT-PCR assays 3 mos apart are documented or until relapse.*

* All groups will have BM exams q 3 mos x 2 yrs, then q 6 mos x 3 yrs, and at relapse.  Pts who do not achieve a negative RT-PCR assay and who do not relapse will continue Gleevec maintenance indefinitely.  Pts who are RT-PCT negative prior to Course VI will continue therapy until a 2nd consecutive negative RT-PCR assay is documented.

Eligibility

• Unequivocal histol dx of ALL.

• Detection of t(9;22)(q34;q11) or 3-way variant by metaphase cytogenetics or BCR-ABL positive by molecular analysis (RT-PCR or FISH).

• Complete or partial remission following 1 course of induction chemo w/intensive 4 or 5 drug regimen (w/ or w/o imatinib mesylate) on CALGB or SWOG protocol for previously untreated ALL pts.  NOTE:  Double induction regimen of SWOG S0333 is considered 1 course of induction chemo for purpose of this eligibility criterion.

  OR

  Complete or partial remission following 1 course of therapy on any standard induction regimen (w/ or w/o imatinib mesylate) w/o prior enrollment on a cooperative group frontline protocol.  In these cases, documentation of Ph+ positivity may occur outside CALGB or SWOG lab.  NOTE:  CALGB institutions must enroll pts on CALGB 9862 and initial sample submission for the companion trial must occur at same time as enrollment on CALGB C10001.  Enrollment on CALGB 8461 & 9665 is not required.

• Age >15 and <60.

• No >6 wks of prior imatinib mesylate during induction therapy b/f study enrollment.

• No pregnant or nursing women.  Men/Women of reproductive potential must use effective contraception until 3 mos after last dose of Gleevec. 

• PRESTUDY REQUIREMENTS (w/i 5 days pre-study):

  • H&P, pulse, BP, temp, ht, wt, BSA, perf status

  • Tumor msmts (liver, spleen, lymph nodes, & mediastinal mass [if applicable])

  • CBC/diff/platelets

  • Serum creat, BUN, lytes

  • PT, PTT

  • SGOT, SGPT, alk phos, bili, LDH

  • Uric acid, PO₄

  • Total protein, albumin

  • EKG

  • µ-HCG or Serum HCG (if childbearing potential)

  • BM histol review

  • CXR (PA & Lat)

  • CSF cell count, CSF protein & glucose (as clinically indicated)

  • Cytogenetics

  • BM asp/bx

• Signed informed consent.