Bone marrow transplantation depleted of T cells followed by repletion with incremental doses of donor lymphocytes for relapsing patients with chronic myeloid leukemia: a therapeutic strategy.

BACKGROUND: For patients with chronic myeloid leukemia (CML), long-term survival after stem cell transplantation requires adequate control of graft-versus-host disease (GVHD) and disease recurrence. Relapsing patients respond to donor lymphocyte infusion (DLI) but develop life-threatening complications. METHODS: Patients with CML in first chronic phase received bone marrow (n = 14) or peripheral blood progenitor cell transplants (n = 4) from HLA-identical siblings. GVHD prophylaxis was by ex vivo T-cell depletion with CAMPATH 1G. If disease recurred, donors' mononuclear cells were collected by apheresis, the CD3 samples commencing at 10(6)/kg were aliquoted at half-log increment intervals, cryopreserved, and infused until disease clearance. RESULTS: Eighteen patients (median age: 32.5 years) received transplants. All engrafted without procedure-related mortality. Fourteen patients relapsed, and 13 entered the DLI program. Two developed extensive GVHD after single schedule infusions ranging from 89x10(6) to 670x10(6) mononuclear cells/kg, and one survives in complete remission (CR). The rest, treated with incremental dose DLI, experienced no acute toxicities. One, who had developed grade III steroid-responsive GVHD, died in CR2 from opportunistic infections. Steroids reversed limited cutaneous GVHD and elevated liver enzymes in five patients. Three others developed pancytopenia, and two restored blood counts only after donor peripheral blood progenitor cell infusions. Molecular CR2 was established in 12/13 patients, occurring in 10/11 (91%) on the incremental program at a median accumulation of 67 (range: 5-166) x10(6) CD3 cells/kg. Sixteen of 18 (89%) survive at median of 854.5 days from bone marrow transplantation, 4 in CR1 and 10 in CR2 at a median disease-free survival (for remission 2) duration of 341 days. The median combined disease-free survival of the 14 patients in CR 1+2 is 660 days, with 99% average performance status. CONCLUSIONS: Escalating DLI leads to safe new molecular CR in most CML relapse patients. These results raise the possibility of using "safe" transplantation programs of T-cell depletion, that include graded DLI as prevention against disease recurrence.

Modulation of granulocyte apoptosis can influence the resolution of inflammation.

Apoptosis of granulocytes and the subsequent clearance of apoptotic cells are important processes for the successful resolution of inflammation. Signalling pathways, including those involving NF-kappaB (nuclear factor kappaB), MAPK (mitogen-activated protein kinase) and PI3K (phosphoinositide 3-kinase) have been shown to be key regulators of inflammatory cell survival and apoptosis in vitro. In addition, manipulation of such pathways in vivo has indicated that they also play a role in the resolution of inflammation. Furthermore, manipulation of proteins directly involved in the control of apoptosis, such as Bcl-2 family members and caspases, can be targeted in vivo to influence inflammatory resolution. Recently, it has been shown that CDK (cyclin-dependent kinase) inhibitor drugs induce caspase-dependent human neutrophil apoptosis possibly by altering levels of the anti-apoptotic Bcl-2 family member, Mcl-1. Importantly, CDK inhibitor drugs augment the resolution of established 'neutrophil-dominant' inflammation by promoting apoptosis of neutrophils. Thus manipulation of apoptotic pathways, together with ensuring macrophage clearance of apoptotic cells, appears to be a viable pharmacological target for reducing established inflammation.