Allogeneic Hematopoietic Cell Transplantation for Peripheral T Cell Lymphoma

Description

Background

Mature neoplasms of T and/or natural killer cells, collectively called peripheral T-cell lymphomas (PTCL), are often poorly responsive to chemotherapy and therefore associated with significant morbidity and mortality.

Allogeneic hematopoietic cell transplantation (HCT) has the potential to cure PTCL but the optimal approach to HCT for these diseases requires ongoing investigation

Objectives

For subjects on the reduced-intensity conditioning (RIC/mRIC) arms, to estimate the progression-free survival

For subjects on the immunosuppression-only conditioning (IOC) and ATL/RIC arms, because they are high risk patients, to preliminarily estimate the proportion who are progression free at one year.

Eligibility

Patients age >= 12 years

PTCL that is relapsed or refractory to prior therapy and/or PTCL of a risk score where upfront allo HCT in first remission is reasonable (PIT score of intermediate-low risk or higher or supported by clinical practice guidelines)

At least one potentially suitable 7-8/8 HLA-matched related or unrelated donor (at HLA A, B, C, and DR), or an HLA-haploidentical related donor

Adequate end-organ function

Not pregnant or breastfeeding

Design

There will be four recipient treatment arms that vary in approach, although all with the same backbone of conditioning and GVHD prophylaxis:

Immunosuppression-only conditioning (IOC) arm for high-risk subjects

Reduced-intensity conditioning (RIC) arm for those deemed not high-risk and able to tolerate RIC and without adult T cell leukemia/lymphoma (ATL)

mRIC arm for patients eligible for the RIC arm, as a modified expansion upon completion of the RIC arm

ATL-RIC arm for patients with a diagnosis of ATL

IOC arm: equine anti-thymocyte globulin (e-ATG) 40 mg/kg/day IV on days -14 and -13, pentostatin 4 mg/m^2/day IV on days -9 and -5, low-dose cyclophosphamide (5 mg/kg) orally daily on days -9 through -2

Subjects will be assigned to the IOC arm if there is significant end-organ dysfunction present and it is felt that a conditioning regimen that includes busulfan would likely be associated with intolerable or life-threatening toxicities for the patient. Patients will also be assigned to the IOC arm if they possess a DNA repair defect, telomere maintenance defect, or familial cancer predisposition syndrome that necessitates limiting chemotherapy as much as possible to prevent future cancer risk.

RIC arm: e-ATG 40 mg/kg/day IV on days -14 and -13, pentostatin 4 mg/m^2/day IV on days -11 and -7, low-dose cyclophosphamide (5 mg/kg) orally daily on days -11 through -4; busulfan IV, pharmacokinetically dosed, on days -3 and -2.

mRIC arm: e-ATG 40 mg/kg/day IV on days -14 and -13, pentostatin 4 mg/m^2/day IV on days -11 and -7, low-dose cyclophosphamide (5 mg/kg) orally daily on days -11 through -4; busulfan IV, pharmacokinetically dosed, on days -3 and -2, G-CSF 5 mcg/kg/day subcutaneous on days -12, -8, and -4.

ATL-RIC arm: e-ATG 40 mg/kg/day IV on days -14 and -13, pentostatin 4 mg/m^2/day IV on days -11 and -7, low-dose cyclophosphamide (5 mg/kg) orally daily on days -11 through -4; busulfan IV, pharmacokinetically dosed, on days -3 and -2, G-CSF 5 mcg/kg/day subcutaneous on days -12, -8, and -4, ruxolitinib 45 mg/day from day -12 through day -2, and zidovudine 300 mg orally three times a day from day -1 through day +50.

Peripheral blood stem cells are the preferred graft source, although bone marrow is permitted

GVHD prophylaxis: Post-transplantation cyclophosphamide (PTCy) on days +3 and +4 (50 mg/kg/day on RIC arm, mRIC, and ATL-RIC arms and 25 mg/kg/day on the IOC arm, with the option of 25 mg/kg/day on the RIC arm). Sirolimus on days +5 through +60 (RIC arm, mRIC arm, IOC arm). Patients with somatic mutations in the Akt/mTOR pathway may receive tacrolimus days +5 through +60 instead of sirolimus on the RIC, mRIC, or IOC arms. Mycophenolate mofetil (MMF) on days +5 through +25 on the RIC, IOC, and mRIC arms; MMF will not be given on the ATL-RIC arm. Patients on the ATL-RIC arm will receive tacrolimus on days +5 through +50 and ruxolitinib 15 mg/day from days +5 through +35, 10 mg/day from days +36 through +60, and 5 mg/day from days +61 through +70.

Details