Chemotherapy, Imatinib Mesylate, and Peripheral Stem Cell Transplantation in Treating Patients With Newly Diagnosed Acute Lymphoblastic Leukemia

A Phase II Trial of Sequential Chemotherapy, Imatinib Mesylate (Gleevec, STI571) (NSC # 716051), and Transplantation for Adults With Newly Diagnosed Ph+ Acute Lymphoblastic Leukemia by the CALGB and SWOG

This phase II trial studies how well giving imatinib mesylate together with chemotherapy and peripheral stem cell transplantation works in treating patients with newly diagnosed acute lymphoblastic leukemia. Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Imatinib mesylate may stop the growth of cancer cells by blocking the enzymes necessary for cancer cell growth. Giving imatinib mesylate together with chemotherapy and peripheral stem cell transplantation may be an effective treatment for acute lymphoblastic leukemia.

Study Overview

• Status: Completed
• Conditions: Adult Acute Lymphoblastic Leukemia in Remission
• Intervention / Treatment: Other: laboratory biomarker analysis; Drug: cyclophosphamide; Drug: etoposide; Drug: cytarabine; Drug: vincristine sulfate; Biological: filgrastim; Radiation: total-body irradiation; Drug: tacrolimus; Procedure: allogeneic hematopoietic stem cell transplantation; Procedure: peripheral blood stem cell transplantation; Procedure: autologous hematopoietic stem cell transplantation; Drug: imatinib mesylate; Drug: leucovorin calcium; Drug: methotrexate

Detailed Description

PRIMARY OBJECTIVES:

I. Determine the activity of imatinib mesylate (Gleevec) to prolong disease-free survival (DFS) and overall survival in acute lymphoblastic leukemia (ALL) patients with t(9;22).

II. Determine the ability of imatinib mesylate (Gleevec) to produce or maintain a BCR-ABL-negative status, as judged by real-time-polymerase chain reaction (RT-PCR) following sequential chemotherapy, imatinib mesylate (Gleevec) and transplantation.

III. Determine the feasibility of collecting adequate peripheral blood stem cells for autologous transplantation following imatinib mesylate (Gleevec) therapy.

IV. Study the safety and efficacy of autologous peripheral stem cell transplantation following therapy with imatinib mesylate (Gleevec).

V. Study the safety and efficacy of allogeneic stem cell transplantation following therapy with imatinib mesylate (Gleevec).

VI. Study the safety and efficacy of imatinib mesylate (Gleevec) administered after allogeneic or autologous stem cell transplant.

OUTLINE:

COURSE I (remission induction): Patients receive 1 course of front-line induction therapy on a Cancer and Leukemia Group B (CALGB)/Southwest Oncology Group (SWOG) protocol prior to enrollment.

COURSE II (imatinib mesylate): Patients receive imatinib mesylate orally (PO) twice daily on days 1-28.

COURSE III (CNS prophylaxis): Within 7 days after completing course II, patients receive methotrexate intrathecally (IT), methotrexate intravenously (IV) over 3 hours, and vincristine sulfate IV on days 1, 8, and 15; methotrexate PO every 6 hours on days 1-2, 8-9, and 15-16; leucovorin calcium IV on days 2, 9, and 16; and leucovorin calcium PO every 6 hours on days 3, 4, 10, 11, 17, and 18.

COURSE IV (imatinib mesylate): After blood counts recover after completion of course III, patients receive imatinib mesylate as in course II.

COURSE V: Patients undergo allogeneic peripheral blood stem cell transplantation (PBSCT), autologous PBSCT, or no PBSCT.

COURSE Va (allogeneic PBSCT for patients with human leukocyte antigen [HLA]-matched sibling donor): Beginning 3-10 days after completion of course IV, patients with an HLA-matched sibling donor undergo total body irradiation (TBI) 2-3 times daily on days -7 to -4. Patients receive etoposide IV over 4 hours on day -3. Patients then undergo PBSCT on day 0. Patients then receive graft-vs-host disease prophylaxis with tacrolimus IV continuously on days -1 to 56 (or IV continuously on days -1 to 14 and then PO or IV every 12 hours on days 15-56) followed by a taper. Patients also receive methotrexate IV on days 1, 3, and 6, and filgrastim subcutaneously (SC) beginning on day 4 and continuing until blood counts recover.

COURSE Vb (autologous PBSCT for patients without HLA-matched sibling donor): Beginning 3-10 days after completion of course IV, patients without an HLA-matched sibling donor receive etoposide IV continuously and cytarabine IV over 2 hours on days 1-4. Patients also receive filgrastim SC beginning on day 14 and continuing until PBSC collection is complete. Patients receive imatinib mesylate PO twice daily beginning after completion of PBSC collection and continuing until 3 days before PBSCT. Patients then undergo TBI 2-3 times daily on days -8 to -5. Patients receive etoposide IV over 4 hours on day -4 and cyclophosphamide IV over 2 hours on day -2. Patients undergo PBSCT on day 0. Patients receive filgrastim SC beginning on day 0 and continuing until blood counts recover.

COURSE Vc (no transplantation for patients who are not transplant candidates): Beginning 3-10 days after completion of course IV, patients who are not candidates for PBSCT receive etoposide IV over 4 hours and cytarabine IV over 2 hours on days 1-4. Patients also receive filgrastim SC once or twice a day beginning on day 14 and continuing until blood counts recover.

COURSE VI: Patients receive imatinib mesylate PO once or twice daily beginning on day 30 post transplantation or on day 30 if no transplantation received and continuing for at least 1 year or until patient has 2 consecutive negative reverse transcriptase-polymerase chain reaction assays at least 3 months apart or until relapse.

After completion of study treatment, patients are followed up monthly for 1 year, every 3 months for 2 years, every 6 months for 2 years, then yearly for 5 years.

• Study Type: Interventional
• Enrollment (Actual): 58
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • Blood and Marrow Transplant Group of Georgia
  • Illinois
    • Bloomington, Illinois, United States, 61701
      • Saint Joseph Medical Center
    • Canton, Illinois, United States, 61520
      • Graham Hospital Association
    • Carthage, Illinois, United States, 62321
      • Memorial Hospital
    • Chicago, Illinois, United States, 60637
      • University of Chicago
    • Chicago, Illinois, United States, 60640
      • Weiss Memorial Hospital
    • Eureka, Illinois, United States, 61530
      • Eureka Hospital
    • Galesburg, Illinois, United States, 61401
      • Galesburg Cottage Hospital
    • Galesburg, Illinois, United States, 61401
      • Illinois CancerCare Galesburg
    • Havana, Illinois, United States, 62644
      • Mason District Hospital
    • Hopedale, Illinois, United States, 61747
      • Hopedale Medical Complex - Hospital
    • Macomb, Illinois, United States, 61455
      • Mcdonough District Hospital
    • Maywood, Illinois, United States, 60153
      • Loyola University Medical Center
    • Normal, Illinois, United States, 61761
      • Community Cancer Center Foundation
    • Normal, Illinois, United States, 61761
      • Bromenn Regional Medical Center
    • Ottawa, Illinois, United States, 61350
      • Illinois CancerCare-Ottawa Clinic
    • Ottawa, Illinois, United States, 61350
      • Ottawa Regional Hospital and Healthcare Center
    • Pekin, Illinois, United States, 61554
      • Pekin Cancer Treatment Center
    • Pekin, Illinois, United States, 61554
      • Pekin Hospital
    • Peoria, Illinois, United States, 61637
      • OSF Saint Francis Medical Center
    • Peoria, Illinois, United States, 61615
      • Illinois CancerCare-Peoria
    • Peoria, Illinois, United States, 61614
      • Proctor Hospital
    • Peoria, Illinois, United States, 61603
      • Methodist Medical Center of Illinois
    • Peoria, Illinois, United States, 61615
      • Illinois Oncology Research Association CCOP
    • Peru, Illinois, United States, 61354
      • Illinois Valley Hospital
    • Princeton, Illinois, United States, 61356
      • Perry Memorial Hospital
    • Spring Valley, Illinois, United States, 61362
      • Saint Margaret's Hospital
  • Indiana
    • Fort Wayne, Indiana, United States, 46845
      • Fort Wayne Medical Oncology and Hematology Inc-Parkview
  • Kansas
    • Chanute, Kansas, United States, 66720
      • Cancer Center of Kansas - Chanute
    • Dodge City, Kansas, United States, 67801
      • Cancer Center of Kansas - Dodge City
    • El Dorado, Kansas, United States, 67042
      • Cancer Center of Kansas - El Dorado
    • Kansas City, Kansas, United States, 66112
      • Providence Medical Center
    • Kingman, Kansas, United States, 67068
      • Cancer Center of Kansas-Kingman
    • Lawrence, Kansas, United States, 66044
      • Lawrence Memorial Hospital
    • Newton, Kansas, United States, 67114
      • Cancer Center of Kansas - Newton
    • Olathe, Kansas, United States, 66061
      • Radiation Oncology Center of Olathe
    • Overland Park, Kansas, United States, 66210
      • Radiation Oncology Practice Corporation Southwest
    • Parsons, Kansas, United States, 67357
      • Cancer Center of Kansas - Parsons
    • Pratt, Kansas, United States, 67124
      • Cancer Center of Kansas - Pratt
    • Salina, Kansas, United States, 67401
      • Salina Regional Health Center
    • Salina, Kansas, United States, 67401
      • Cancer Center of Kansas - Salina
    • Wellington, Kansas, United States, 67152
      • Cancer Center of Kansas - Wellington
    • Wichita, Kansas, United States, 67208
      • Cancer Center of Kansas-Wichita Medical Arts Tower
    • Wichita, Kansas, United States, 67208
      • Associates In Womens Health
    • Wichita, Kansas, United States, 67214
      • Cancer Center of Kansas - Main Office
    • Wichita, Kansas, United States, 67214
      • Via Christi Regional Medical Center
    • Wichita, Kansas, United States, 67214
      • Wichita CCOP
    • Winfield, Kansas, United States, 67156
      • Cancer Center of Kansas - Winfield
  • Maine
    • Bangor, Maine, United States, 04401
      • Eastern Maine Medical Center
  • Massachusetts
    • Beverly, Massachusetts, United States, 01915
      • Beverly Hospital
    • Gloucester, Massachusetts, United States, 01930
      • Addison Gilbert Hospital
    • Worcester, Massachusetts, United States, 01605
      • Commonwealth Hematology Oncology PC-Worcester
  • Missouri
    • Independence, Missouri, United States, 64057
      • Centerpoint Medical Center LLC
    • Kansas City, Missouri, United States, 64111
      • Saint Luke's Cancer Institute
    • Kansas City, Missouri, United States, 64114
      • Radiation Oncology Practice Corporation South
    • Kansas City, Missouri, United States, 64154
      • Radiation Oncology Practice Corporation - North
    • Liberty, Missouri, United States, 64068
      • Liberty Hospital
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • Montana
    • Billings, Montana, United States, 59101
      • Saint Vincent Healthcare
    • Billings, Montana, United States, 59101
      • Northern Rockies Radiation Oncology Center
    • Billings, Montana, United States, 59101
      • Montana Cancer Consortium CCOP
    • Billings, Montana, United States, 59102
      • Hematology-Oncology Centers of the Northern Rockies PC
    • Billings, Montana, United States, 59107-7000
      • Billings Clinic
    • Billings, Montana, United States, 59107
      • Deaconess Medical Center
    • Bozeman, Montana, United States, 59715
      • Bozeman Deaconess Hospital
    • Bozeman, Montana, United States, 59715
      • Bozeman Deaconess Cancer Center
    • Bozeman, Montana, United States, 59715
      • Internal Medicine of Bozeman
    • Butte, Montana, United States, 59701
      • Saint James Community Hospital and Cancer Treatment Center
    • Great Falls, Montana, United States, 59405
      • Great Falls Clinic
    • Great Falls, Montana, United States, 59405
      • Berdeaux, Donald MD (UIA Investigator)
    • Helena, Montana, United States, 59601
      • Saint Peter's Community Hospital
    • Kalispell, Montana, United States, 59901
      • Kalispell Regional Medical Center
    • Kalispell, Montana, United States, 59901
      • Glacier Oncology PLLC
    • Kalispell, Montana, United States, 59901
      • Kalispell Medical Oncology
    • Missoula, Montana, United States, 59802
      • Saint Patrick Hospital - Community Hospital
    • Missoula, Montana, United States, 59804
      • Guardian Oncology and Center for Wellness
    • Missoula, Montana, United States, 59801
      • Community Medical Hospital
    • Missoula, Montana, United States, 59802
      • Montana Cancer Specialists
  • New Hampshire
    • Keene, New Hampshire, United States, 03431
      • Cheshire Medical Center-Dartmouth-Hitchcock Keene
    • Rochester, New Hampshire, United States, 03867
      • Frisbie Hospital
  • New York
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Institute
    • Manhasset, New York, United States, 11030
      • North Shore University Hospital
    • Manhasset, New York, United States, 11030
      • North Shore-LIJ Health System CCOP
    • New Hyde Park, New York, United States, 11040
      • Long Island Jewish Medical Center
    • New Hyde Park, New York, United States, 11040
      • North Shore-LIJ Health System/Center for Advanced Medicine
    • New York, New York, United States, 10065
      • Weill Medical College of Cornell University
    • Oswego, New York, United States, 13126
      • Oswego Hospital
    • Rochester, New York, United States, 14642
      • University of Rochester
    • Syracuse, New York, United States, 13210
      • State University of New York Upstate Medical University
  • North Carolina
    • Kinston, North Carolina, United States, 28501
      • Kinston Medical Specialists PA
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University Health Sciences
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University Medical Center
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15224-1791
      • Western Pennsylvania Hospital
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Vermont
    • St. Johnsbury, Vermont, United States, 05819
      • Northeastern
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University
  • Wyoming
    • Sheridan, Wyoming, United States, 82801
      • Welch Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years to 59 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Unequivocal histologic diagnosis of ALL
• Detection of the t(9;22)(q34;q11) or 3-way variant by metaphase cytogenetics or BCR-ABL positive by molecular analysis (RT-PCR or fluorescence in situ hybridization [FISH})

• Prior Therapy:

  • Complete or partial remission following one course of induction chemotherapy with an intensive 4 or 5 drug regimen (with or without imatinib mesylate) on a CALGB or SWOG ALL protocol for previously untreated ALL patients

    • Note: The double induction regimen of SWOG S0333 is considered to be one course of induction chemotherapy for the purpose of this eligibility criterion; therefore, patients from S0333 may be eligible for this study only after completing the entire double induction regimen

  • Complete or partial remission following one course of therapy on any standard induction regimen (with or without imatinib mesylate) without prior enrollment on a cooperative group frontline protocol; in these instances, documentation of Philadelphia chromosome (Ph)+ positivity may occur outside a CALGB or SWOG laboratory

    • Note: CALGB institutions must enroll patients on CALGB 9862 and submission of an initial sample for the companion trial must occur at time of enrollment on CALGB C10001; enrollment on companion studies CALGB 8461 and 9665 is not required
• No more than six weeks of prior imatinib mesylate during induction therapy before study enrollment
• Non-pregnant and non-nursing; treatment under this protocol would expose an unborn child to significant risks; women and men of reproductive potential should agree to use an effective means of birth control and contraception should continue for three months after the last dose of imatinib mesylate (Gleevec) to allow complete clearance of drug and its principle metabolites from the body; in women of childbearing potential, a pregnancy test will be required at study entry

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (imatinib mesylate, chemotherapy, PBSCT); See Detailed Description.

Other: laboratory biomarker analysis; Correlative studies; Drug: cyclophosphamide; Given IV; Other Names: Cytoxan; Endoxan; CPM; CTX; Endoxana; Drug: etoposide; Given IV; Other Names: EPEG; VP-16; VP-16-213; Drug: cytarabine; Given IV; Other Names: Cytosar-U; cytosine arabinoside; ARA-C; arabinofuranosylcytosine; arabinosylcytosine; Drug: vincristine sulfate; Given IV; Other Names: VCR; leurocristine sulfate; Vincasar PFS; Biological: filgrastim; Given SC; Other Names: G-CSF; Neupogen; Radiation: total-body irradiation; Undergo TBI; Other Names: TBI; Drug: tacrolimus; Given IV or PO; Other Names: Prograf; FK 506; Procedure: allogeneic hematopoietic stem cell transplantation; Undergo allogeneic PBSCT; Procedure: peripheral blood stem cell transplantation; Undergo PBSCT; Other Names: PBPC transplantation; PBSC transplantation; peripheral blood progenitor cell transplantation; transplantation, peripheral blood stem cell; Procedure: autologous hematopoietic stem cell transplantation; Undergo autologous PBSCT; Drug: imatinib mesylate; Given PO; Other Names: Gleevec; CGP 57148; Glivec; Drug: leucovorin calcium; Given IV and PO; Other Names: CF; CFR; LV; Drug: methotrexate; Given IT and IV; Other Names: amethopterin; Folex; methylaminopterin; Mexate; MTX

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease Free Survival	Disease-free survival (DFS) was measured as the interval from achievement of complete remission (CR) until relapse or death, regardless of cause; patients alive and in CR were censored at last follow-up. DFS was estimated using the Kaplan Meier method. A complete remission (CR) was defined as recovery of morphologically normal bone marrow and blood counts (i.e., neutrophils >= 1.5 x 10^9/L and platelets > 100 x 10^9/L) and no circulating leukemic blasts or evidence of extramedullary leukemia and persisting for at least one month.	Duration of treatment (up to 10 years)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	Overall survival (OS) as the interval from the on-study date until death. OS was estimated using the Kaplan Meier method.	Duration of study (up to 10 years)
Number of Participants Who Achieved a BCR-ABL Response at 12 Months	BCR-ABL response is defined in two ways: complete molecular response (CMR) and major molecular response (MMR). Complete Molecular Response is defined as a Bcr-Abl (a fusion of gene of Bcr and ABl genes) ratio ≤0.0032% on the International Scale Bcr = breakpoint cluster gene Abl = abelson proto-oncogene MMR is defined as Bcr-Abl (A fusion gene of the breakpoint cluster region [Bcr] gene and Abelson proto-oncogene [Abl] genes) transcript ratio ≤0.1% (≥ 3 log reduction of BCR-ABL transcripts from a standardized baseline), as detected by reverse transcriptase polymerase chain reaction [RT-PCR] (performed centrally).	12 months
5 Year Disease-free Survival for Autologous & Allogeneic Transplant Groups	Percentage of patients who achieved a complete remission (CR) and were alive and relapse free at 5 years. The 5-year progression free survival was estimated using the Kaplan Meier method.	5 years from CR
5 Year Overall Survival for Autologous & Allogeneic Transplant Groups	Percentage of patients who were alive at 5 years. The 5-year progression free survival was estimated using the Kaplan Meier method.	5 years from registration

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Meir Wetzler, Cancer and Leukemia Group B

Publications and helpful links

General Publications

• Mims AS, Kohlschmidt J, Borate U, Blachly JS, Orwick S, Eisfeld AK, Papaioannou D, Nicolet D, Mromicronzek K, Stein E, Bhatnagar B, Stone RM, Kolitz JE, Wang ES, Powell BL, Burd A, Levine RL, Druker BJ, Bloomfield CD, Byrd JC. A precision medicine classification for treatment of acute myeloid leukemia in older patients. J Hematol Oncol. 2021 Jun 23;14(1):96. doi: 10.1186/s13045-021-01110-5.
• Wetzler M, Watson D, Stock W, Koval G, Mulkey FA, Hoke EE, McCarty JM, Blum WG, Powell BL, Marcucci G, Bloomfield CD, Linker CA, Larson RA. Autologous transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia achieves outcomes similar to allogeneic transplantation: results of CALGB Study 10001 (Alliance). Haematologica. 2014 Jan;99(1):111-5. doi: 10.3324/haematol.2013.085811. Epub 2013 Sep 27.

Study record dates

Study Major Dates

• Study Start: April 1, 2002
• Primary Completion (Actual): April 1, 2012
• Study Completion (Actual): February 1, 2014

Study Registration Dates

• First Submitted: June 6, 2002
• First Submitted That Met QC Criteria: January 26, 2003
• First Posted (Estimate): January 27, 2003

Study Record Updates

• Last Update Posted (Estimate): November 24, 2014
• Last Update Submitted That Met QC Criteria: November 13, 2014
• Last Verified: June 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Protective Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Dermatologic Agents; Micronutrients; Protein Kinase Inhibitors; Vitamins; Reproductive Control Agents; Antidotes; Vitamin B Complex; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Calcineurin Inhibitors; Cyclophosphamide; Etoposide; Etoposide phosphate; Leucovorin; Levoleucovorin; Cytarabine; Methotrexate; Vincristine; Imatinib Mesylate; Tacrolimus
• Other Study ID Numbers: NCI-2009-00436 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); U10CA031946 (U.S. NIH Grant/Contract); CDR0000069378; CALGB 10001/SWOG C10001 (Other Identifier: Cancer and Leukemia Group B); CALGB-10001 (Other Identifier: CTEP)