p53/p16-Independent Epigenetic Therapy With Oral Decitabine/Tetrahydrouridine for Refractory/Relapsed Lymphoid Malignancies

Complete disappearance of all detectable clinical evidence of disease, and disease-related symptoms if present prior to therapy

A > 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or extranodal masses. These nodes should be selected according to the following: (a) they should be clearly measurable in at least 2 perpendicular dimensions; (b) they should include mediastinal and retroperitoneal areas of disease whenever these sites are involved.

No increase in the size of other nodes, liver or spleen.

Bone marrow assessment is irrelevant for determination of a PR if the sample was positive prior to treatment. However, if positive, the cell type should be specified, e.g. large-cell lymphoma or small cleaved cell lymphoma.

No new sites of disease

Failing to attain the criteria needed for a PR or CR, but not fulfilling those for progressive disease.

For FDG-avid lymphomas: FDG-PET/CT should be positive at prior sites of disease with no new areas of involvement on the post-treatment CT or FDG-PET/CT.

For variably FDG-avid lymphomas/FDG-avidity unknown: For patients without a pretreatment FDG-PET/CT scan or if the pre-treatment FDG-PET/CT was negative, there must be no change in the size of the previous lesions on the post-treatment CT scan.

For determination of relapsed and progressive disease, lymph nodes should be considered abnormal if the long axis is more than 1.5 cm, regardless of the short axis. If a lymph node has a long axis of 1.1 to 1.5 cm, it should only be considered abnormal if the short axis is more than 1 cm. Lymph nodes < 1 x < 1 cm will not be considered as abnormal for relapse or progressive disease. Treatment decisions in patients with presumed refractory, relapsed or progressive disease should not be made solely on the basis of a single FDG-PET/CT scan without histologic confirmation.

This is measured, only in responders, from the documented beginning of response (CR or PR) to the time of relapse.

Survival is defined as the date of study entry to the date of death. Disease-free survival is measured from the time of occurrence of disease-free state (e.g. the adjuvant setting following surgery or radiation therapy) or attainment of a complete remission) to disease recurrence or death from lymphoma or acute toxicity of treatment. This definition may be complicated by deaths that occur during the follow-up period that are unrelated to the lymphoma and there is controversy as to whether such deaths should be considered as events or censored at the time of occurrence. Whereas it is often possible to identify those deaths related to the lymphoma, there is the potential for bias in the attribution of deaths.

Disease-specific survival (e.g., lymphoma-specific survival, cause-specific survival) is potentially subject to bias because the exact cause of death is not always easy to ascertain. To minimize the risk of bias, the event should be recorded as death from lymphoma, or from toxicity from the drug. Death from unknown causes should be attributed to the drug. For certain trials, time to next lymphoma treatment may be of interest, defined as time from the end of primary treatment until the initiation of the next therapy.

Progression-free Survival (PFS) is defined as the time from entry onto study until lymphoma progression or death from any cause. PFS reflects tumor growth and, therefore, occurs prior to the endpoint of overall survival. In addition, PFS is not confounded by the administration of subsequent therapy. Whether a prolongation of PFS represents direct clinical benefit or a surrogate for clinical benefit depends on the magnitude of the effect and the risk-benefit ratio of the therapy under investigation. Unlike survival, the precise date of progression is generally unknown. It may be defined as the first date of documentation of a new lesion or enlargement of a previous lesion, or the date of the scheduled clinic visit immediately after radiologic assessment has been completed. Where there is missing information, censoring of the data may be defined as the last date at which progression status was adequately assessed or the first date of unscheduled new anti-lymphoma treatment.

Time to progression (TTP) is defined as the time from study entry until lymphoma progression or death due to lymphoma. In TTP, deaths from other causes are censored either at the time of death or at an earlier time of assessment, representing a random pattern of loss from the study. TTP is not as useful as PFS unless the majority of deaths on a study are unrelated to the lymphoma due to the efficacy of the treatment and/or prolonged follow up

Time to treatment failure (event-free survival) is measured from the time from study entry to any treatment failure including discontinuation of treatment for any reason, such as disease progression, toxicity, patient preference, initiation of new treatment without documented progression, or death. This composite endpoint is generally not encouraged by regulatory agencies because it combines efficacy, toxicity and patient withdrawal.