Expanded Cord Blood in Patients in Need of an Allogeneic Stem Cell Transplant

To identify unexpected toxicities associated with transplantation using cord blood cells expanded with UM171/fed-batch culture system by means of history, physical examination and laboratory evaluation. All adverse events will be evaluated for duration, intensity, and causal relationship with the study medication and followed to the end of the study or until resolution.

The feasibility of expanding cord blood units for allogeneic cord blood transplantation in adults will be evaluated by determining the percentage of selected grafts that will be successfully expanded in the absence of technical hurdles such as contamination or unexpected technical failure, and that will meet release criteria and be successfully infused in patients.

Time to neutrophil engraftment is defined as the first day of attainment of an absolute neutrophil count (ANC) ≥ 0.5 x 109/L for 3 consecutive days as per Center for International Blood and Marrow Transplant Research (CIBMTR) standards.

Platelet engraftment is defined as the first day of a sustained platelet count ≥ 20 x 109/L with no platelet transfusion in the preceding 7 days as per CIBMTR standards.

The minimal cord blood unit cell dose (TNC/CD34+) that, once expanded, achieves prompt engraftment as a single cord transplant will be defined as the lower cord blood cell dose that satisfies all of the following conditions for umbilical cord blood (UCB) dose reduction , i.e.:

• Minimum of 3 patients who will have received a single cord transplant (no back-up cord),
• Cord to be expanded contains less than 2.0 x 105 CD34+/kg at thaw pre-expansion in cohort 1 and less than 1.0 x 105 CD34+/kg at thaw pre-expansion in cohort 2
• Engraftment must have occurred within 18 days.

Time to neutrophil and platelet engraftment will be correlated to the CD34+ and the CD34+CD45RA- dose (which includes all human hematopoietic stem cells (HSCs): long term and short term repopulating cells) contained in the expanded graft. Expansion and cultures might change the characteristics and behaviour of CD34+ cells, hence the need to look at the correlation between primitive CD34+CD45RA- subpopulation and engraftment.

The patient will be declared as having developed primary graft failure if:

• Lack of neutrophil engraftment by day 42.
• Infusing another stem cell source prior to day 42 (other than the nonmanipulated cord and back up cord).
• < 5% donor chimerism after day +14 up to and including day +42 after transplant.
• Death from day 28 to 42 without neutrophil engraftment.

Secondary or late graft failure when:

• ANC drops below 0.5 x 109/L for 14 consecutive days unresponsive to growth colony stimulating factor (G-CSF) witout identifiable cause (medication, viral infection, vitamin deficience or other)

This evaluation will be performed in lymphoid and myeloid cells to determine the expanded cord's role in short and long term engraftment in patients. Cell sorting to examine chimerism of different cell subsets will be performed with complex of differentiation (CD) such as CD3, CD33, CD56, CD14 and CD19 to determine the proportions in which donor's immune cells are represented in the graft recipient.

Donor cell engraftment is defined as donor cell (lymphoid or myeloid) chimerism ≥ 5% by day +42 post transplant. Full donor chimerism is defined as ≥ 95% donor myeloid and lymphoid chimerism.

The incidence of acute and chronic GVHD will be evaluated throughout the study using NIH criteria. Acute GVHD will be defined as classic acute (time of onset of symptoms ≤ 100 days) or persistent, recurrent, or late onset acute GVHD (time of onset of symptoms > 100 days) as defined by the NIH.

Patients will be assessed for the presence of chronic GVHD at each medical evaluation. Data will be collected directly from providers and chart review according to the recommendations of the NIH Consensus Conference.

any grade 3 infection will be tabulated as well as any of the following infections requiring systemic therapy will be captured: invasive candidiasis, aspergillus, other invasive fungi, cytomegalovirus (CMV), adenovirus, Epstein-Barr virus (EBV), Human herpes virus (HHV-6), herpes simplex (HSV), varicella-zoster virus (VZV), Pneumocystis carinii pneumonitis (PCP), toxoplasmosis and mycobacterium. Severity of infections will be graded according to the Technical Manual of Procedure of the Blood and Marrow Transplant Clinical Trials Network.

Multiparametric flow cytometry to quantify the proportion of naïve (CD45RA+/CD27+) and memory (CD45RA-/CD27+) cells.

The outcome (success or failure) in B cell recovery will be evaluated by flow cytometry, immunoglobulin measurements and PCR for donor cell chimerism.

The outcome (success or failure) in NK cell recovery will be evaluated by flow cytometry and PCR for donor cell chimerism.

Incidence of TRM will be monitored throughout the study and in particular at 100 days, 1, 2, and 3 years post transplantation. If it should exceed 30% at day 100, stopping rules may apply that could prematurely terminate the trial.

Progression free survival (PFS) will be monitored throughout the study and in particular at 1, 2, and 3 years post-transplant.

PFS will be measured from time of transplant until progression, death or last follow-up.

PFS: an event is defined as relapse/progression or death.

Overall survival (OS) will be monitored throughout the study and in particular at 1, 2, and 3 years post-transplant.

OS will be measured from time of transplant until progression, death or last follow-up.

OS: an event is defined as death.

Patients will be monitored for the occurrence of engraftment and preengraftment syndromes (ES and PES) as well as the necessity for treatment. Diagnostic criteria for ES are noninfectious fever plus any of the following: skin rash, pulmonary infiltrates, hepatic dysfunction, or diarrhea.