Hematopoietic Cell Transplantation for Patients With Hematologic Malignancies Using Related, HLA-Haploidentical Donors

Nonmyeloablative Hematopoietic Stem Cell Transplantation (SCT) for High-Risk Hematologic Malignancies With Related, HLA-Haploidentical Donors: A Phase II Trial of Immunosuppression With Cyclophosphamide Administered Before and After SCT

The purpose of this study is to determine if engraftment can be achieved safely in patients with high-risk hematologic malignancies who undergo non-myeloablative transplant with peripheral stem cells from Human Leukocyte Antigen (HLA) haploidentical donors with pre and post-transplant cyclophosphamide as immunosuppression.

Study Overview

• Status: Recruiting
• Conditions: Hematologic Neoplasms
• Intervention / Treatment: Drug: Cyclophosphamide; Other: Hematopoietic Stem Cell Transplantation,

Detailed Description

It is important to extend the option of nonmyeloablative, hematopoietic stem cell transplantation (HSCT) for potential therapy of hematologic malignancies to patients who do not have an HLA-matched donor. Almost all patients would have a related donor identical for one HLA haplotype (haploidentical) and mismatched at HLA-A, B or DR of the unshared haplotype. Thus far, nonmyeloablative HSCT from HLA-mismatched donors has been associated with a high rate of graft failure and graft-versus-host disease (GVHD). In this protocol, we will use a combination of immunosuppressive agents including cyclophosphamide administered before and after HSCT to facilitate engraftment and to delete highly alloreactive T-cell clones presumably involved in GVHD.

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Rocco Pastano, MD; Email: rocco.pastano@ieo.it

Study Locations

• Italy
  • Milan, Italy, 20141
    • Recruiting
    • European Institute of Oncology
    • Contact: Rocco Pastano, MD; Phone Number: +390257489538; Email: rocco.pastano@ieo.it
    • Principal Investigator: Rocco Pastano, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients ≤70 years old
• Eligible diagnoses:
• CML in AP
• AML with high-risk cytogenetics [del(5q)/-5, del(7q)/-7, abnormal 3q, 9q, 11q, 20q, 21q, 17p, t(6:9), t(9;22), complex karyotypes (≥3 abnormalities)] in CR1
• AML ≥ CR2; patients should have <5% marrow blasts at the time of transplant
• High-risk ALL defined as:

CR1 with high-risk cytogenetics t(9;22), t(8;14), t(4;11), t(1;19) for adult patients >4 wk to achieve CR1

≥ CR2 Patients should have <5% marrow blasts at the time of transplant

• MDS (>int-1 per IPSS) after ≥ 1 prior cycle of induction chemotherapy; should have<5% marrow blasts at the time of transplant
• MM Stage II or III patients who have progressed after an initial response to chemotherapy or autologous HSCT or MM patients with refractory disease who may benefit from tandem autologous-nonmyeloablative allogeneic transplant
• CLL, NHL or HD who are ineligible for autologous HSCT or who have resistant/refractory disease and who may benefit from tandem autologous nonmyeloablative allogeneic transplant.
• Patients who have received a prior allogeneic HSCT and who have either rejected their grafts or who have become tolerant of their grafts with no active GvHD requiring immunosuppressive therapy could be enrolled

Exclusion Criteria:

• Patients with suitably matched related or unrelated donors
• Patients with conventional transplant options (a conventional transplant should be the priority for eligible patients ≤ 50 yr of age who have a related donor mismatched for a single HLA-A, -B or DRB1 antigen)
• CNS involvement with disease refractory to intrathecal chemotherapy
• Presence of active, serious infection (e.g., mucormycosis, uncontrolled aspergillosis, tuberculosis)
• Karnofsky Performance Status < 60% for adult patients (Appendix A)

• Patients with the following organ dysfunction:

  • Left ventricular ejection fraction <35%
  • DLCO <35% and/or receiving supplemental continuous oxygen
  • Liver abnormalities: fulminant liver failure, cirrhosis of the liver with evidence of portal hypertension, alcoholic hepatitis, esophageal varices, hepatic encephalopathy, uncorrectable hepatic synthetic dysfunction as evidenced by prolongation of the prothrombin time, ascites related to portal hypertension, bacterial or fungal liver abscess, biliary obstruction, chronic viral hepatitis with total serum bilirubin >3 mg/dL or symptomatic biliary disease.
• HIV-positive patients
• Women of childbearing potential who are pregnant (β-HCG+) or breast feeding
• Fertile men and women unwilling to use contraceptives during and for 12 months post transplant
• Life expectancy severely limited by diseases other than malignancy
• Patients on any other investigational drug at time of enrolment

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: Stem Cell Transplant+Cyclophosphamide; patients with high-risk hematologic malignancies will receive hematopoietic stem cell transplantation from haploidentical donors after treatment with cyclophosphamide	Drug: Cyclophosphamide; 14.5 mg/kg, IV qd on day -6 and -5 and 50 mg/kg, IV on day +3 and +4; Other Names: Endoxan; Other: Hematopoietic Stem Cell Transplantation,; Hematopoietic Stem Cell Transplantation,; Other Names: Stem cell transplantation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Donor engraftment	percentage of donor engraftment after 84 from baseline	Day +84

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence and severity of graft versus host disease	Incidence and severity of graft versus host disease after 200 days from the baseline	up to 200 days after the baseline
Non-relapse-related mortality	incidence of non-relapse-related mortality after 200 days from the baseline	Incidence and severity of graft versus host disease after 200 days from the baseline

Collaborators and Investigators

• Sponsor: European Institute of Oncology
• Investigators: Principal Investigator: Rocco Pastano, MD, European Institute of Oncology

Publications and helpful links

General Publications

• Luznik L, Jalla S, Engstrom LW, Iannone R, Fuchs EJ. Durable engraftment of major histocompatibility complex-incompatible cells after nonmyeloablative conditioning with fludarabine, low-dose total body irradiation, and posttransplantation cyclophosphamide. Blood. 2001 Dec 1;98(12):3456-64. doi: 10.1182/blood.v98.12.3456.
• O'Donnell PV, Luznik L, Jones RJ, Vogelsang GB, Leffell MS, Phelps M, Rhubart P, Cowan K, Piantados S, Fuchs EJ. Nonmyeloablative bone marrow transplantation from partially HLA-mismatched related donors using posttransplantation cyclophosphamide. Biol Blood Marrow Transplant. 2002;8(7):377-86. doi: 10.1053/bbmt.2002.v8.pm12171484.

Study record dates

Study Major Dates

• Study Start: August 1, 2010
• Primary Completion (Estimated): December 1, 2023
• Study Completion (Estimated): December 1, 2023

Study Registration Dates

• First Submitted: June 15, 2011
• First Submitted That Met QC Criteria: June 15, 2011
• First Posted (Estimated): June 16, 2011

Study Record Updates

• Last Update Posted (Actual): June 28, 2023
• Last Update Submitted That Met QC Criteria: June 27, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: Cyclophosphamide; Hematopoietic Stem Cell Transplantation; Haploidentical Donors; High-Risk Hematologic Neoplasms
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Site; Hematologic Diseases; Hematologic Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Cyclophosphamide
• Other Study ID Numbers: IEO S513/110; 2009-018083-94 (EudraCT Number)