Recipients Receiving Better HLA-Matched Hematopoietic Cell Transplantation Grafts, Uncovered by a Novel HLA Typing Method, Have Superior Survival: A Retrospective Study.

HLA matching at an allelic-level resolution for volunteer unrelated donor (VUD) hematopoietic cell transplantation (HCT) results in improved survival and fewer post-transplant complications. Limitations in typing technologies used for the hyperpolymorphic HLA genes have meant that variations outside of the antigen recognition domain (ARD) have not been previously characterized in HCT. Our aim was to explore the extent of diversity outside of the ARD and determine the impact of this diversity on transplant outcome. Eight hundred ninety-one VUD-HCT donors and their recipients transplanted for a hematologic malignancy in the United Kingdom were retrospectively HLA typed at an ultra-high resolution (UHR) for HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1 using next-generation sequencing technology. Matching was determined at full gene level for HLA class I and at a coding DNA sequence level for HLA class II genes. The HLA matching status changed in 29.1% of pairs after UHR HLA typing. The 12/12 UHR HLA matched patients had significantly improved 5-year overall survival when compared with those believed to be 12/12 HLA matches based on their original HLA typing but were found to be mismatched after UHR HLA typing (54.8% versus 30.1%, P = .022). Survival was also significantly better in 12/12 UHR HLA-matched patients when compared with those with any degree of mismatch at this level of resolution (55.1% versus 40.1%, P = .005). This study shows that better HLA matching, found when typing is done at UHR that includes exons outside of the ARD, introns, and untranslated regions, can significantly improve outcomes for recipients of a VUD-HCT for a hematologic malignancy and should be prospectively performed at donor selection.

Complete molecular responses are achieved after reduced intensity stem cell transplantation and donor lymphocyte infusion in chronic myeloid leukemia.

Patients with newly diagnosed chronic phase chronic myeloid leukemia were treated with imatinib mesylate (IM) for 6 to 12 months to establish disease control, before reduced intensity stem cell transplantation (RISCT). Escalating doses of donor lymphocyte infusions were given from 6 months after transplantation to eradicate residual disease. A total of 18 patients entered the study and 15 received RISCT (median follow-up, 31 months). RISCT was well tolerated with rapid engraftment, short inpatient stays, and few readmissions. Viral reactivation was common, although extensive graft-versus-host disease occurred infrequently. Donor lymphocyte infusions were given as part of the RISCT protocol in 13 of 15 patients. BCR-ABL transcripts continued to decrease after RISCT, and 8 (53%) patients achieved sustained undetectable levels. All patients are currently off IM. Although IM is now established as first-line therapy for chronic phase chronic myeloid leukemia, this protocol is a safe, well-tolerated, and effective strategy in these patients. This study is registered at http://www.controlled-trials.com as ISRCTN86187144.

Presence of donor-encoded centromeric KIR B content increases the risk of infectious mortality in recipients of myeloablative, T-cell deplete, HLA-matched HCT to treat AML.

The reported influence of donor Killer-cell Immunoglobulin-like Receptor (KIR) genes on the outcomes of haematopoietic cell transplantation (HCT) are contradictory, in part due to diversity of disease, donor sources, era and conditioning regimens within and between different studies. Here, we describe the results of a retrospective clinical analysis establishing the effect of donor KIR motifs on the outcomes of 119 HLA-matched, unrelated donor HCT for adult acute myeloid leukaemia (AML) using myeloablative conditioning (MAC) in a predominantly T-cell deplete (TCD) cohort. We observed that HCT involving donors with at least one KIR B haplotype were more likely to result in non-relapse mortality (NRM) than HCT involving donors with two KIR A haplotypes (p = 0.019). Upon separation of KIR haplotypes into their centromeric (Cen) and telomeric (Tel) motif structures, we demonstrated that the Cen-B motif was largely responsible for this effect (p = 0.001). When the cause of NRM was investigated further, infection was the dominant cause of death (p = 0.006). No evidence correlating donor KIR B haplotype with relapse risk was observed. The results from this analysis confirm previous findings in the unrelated, TCD, MAC transplant setting and imply a protective role for donor-encoded Cen-A motifs against infection in allogeneic HCT recipients.

Oral sodium clodronate induced osteonecrosis of the jaw in a patient with myeloma.

Bisphosphonate therapy has been shown to significantly reduce the incidence of skeletal complications in patients with myeloma. Several recent reports have described osteonecrosis of the jaw (ONJ) associated with bisphosphonates. These reports mainly demonstrate an association between ONJ and potent i.v. bisphosphonates. We report a case of ONJ in a patient with myeloma, who had only been treated with oral sodium clodronate. While the degree of risk for osteonecrosis in patients taking oral bisphosphonates, such as clodronate, remains uncertain it would be prudent to consider carefully the indications for the use of these agents to minimise the risk of ONJ.

Response to thalidomide in chemotherapy-resistant mantle cell lymphoma: a case report.

Mantle cell lymphoma is an aggressive B-cell lymphoma with a poor median survival despite conventional therapy. Here, we present the case of a patient with multiply relapsed mantle cell lymphoma, having failed treatment with chemotherapy, steroids and rituximab. He was treated with single-agent thalidomide at a dose of 800 mg daily and entered a good partial remission which was maintained for the next 6 months. There is clearly a need for further studies of thalidomide in mantle cell lymphoma to confirm this promising initial result.

Dose escalation therapy in previously untreated patients with multiple myeloma following Z-Dex induction treatment.

A phase I-II study of high-dose (HD) alkylating agents in newly diagnosed patients with multiple myeloma after maximum response to Z-Dex (idarubicin, dexamethasone) therapy and DHAP (cisplatin, HD cytosine arabinoside, dexamethasone), stem cell mobilization is reported. Twenty-six patients, median age 56 years (range 42-66), completed Z-Dex chemotherapy and peripheral blood stem cells (PBSC) were mobilized with DHAP. Patients then preceded to cyclophosphamide (HD Cy: 6 g/m(2)) with granulocyte colony-stimulating factor followed by busulphan-melphalan-conditioned PBSC autograft. Interferon alpha was introduced at 3 months post transplant as maintenance therapy. Six patients failed to complete the full protocol. Median time from diagnosis to transplantation was 8 months (range 6-12). Mean CD34+ cell dose collected was 15.8 x 10(6)/kg (CI 11.8, 19.8). Median time from DHAP to HD-Cy was 6 weeks (range 4-12) and from HD-Cy to transplant was 8 weeks (range 6-12). The median follow-up was 36 months (range 6-63). On an intent-to-treat basis, the response rates were three complete response (CR, 12%), 21 partial response (PR, 80%) and two stable disease (SD, 8%) post Z-Dex, five CR (19%) and 21 PR (81%) post HD-Cy, and 14 CR (54%) and 12 PR (46%) post transplant. The treatment-related mortality (TRM) was 4% (1 patient). Median overall survival (OS) and progression-free survival (PFS) have not been reached; estimated values were 60 and 48 months respectively. The 3-year OS and PFS were 72% and 62%. Actuarial 5-year OS and event-free survival were 49% and 32%. DHAP produces effective PBSC mobilization and sequential HD therapy, including autologous PBSCT, in patients who received Z-Dex; this offers significant durable disease response rates with acceptable TRM.