Yeow-Tee Goh

A phase I/II clinical trial of autologous cytokine-induced killer cells as adjuvant immunotherapy for acute and chronic myeloid leukemia in clinical remission

BACKGROUND AIMS Cytokine-induced killer (CIK) cells have shown remarkable cytotoxicity against various tumors in vitro and in animal studies. We report on the clinical outcome of autologous CIK cells for patients with acute (AML) and chronic (CML) myeloid leukemia in remission. METHODS Eleven of the 13 recruited AML patients undergoing autologous peripheral blood stem cell transplant (autoPBSCT) were given autologous CIK cell infusion upon engraftment post-transplant and followed-up for disease relapse. Eleven CML patients on Imatinib with residual disease detectable by polymerase chain reaction (PCR) were given infusion and monitored by quantitation of the bcr-abl transcript. RESULTS Despite the presence of interferon (IFN)-γ-secreting T cells against various AML- and CML-associated peptides at sporadic time-points and demonstration of in vitro cytotoxicity of CIK cells against autologous and allogeneic AML targets, there was no survival benefit in AML patients post-autoPBSCT given CIK cells compared with historical controls. For CML patients, all continued to have a detectable bcr-abl transcript fluctuating within a range comparable to their pre-treatment baseline, although two had a transient but non-sustainable disappearance of bcr-abl transcript. There were no adverse reactions except for fever within the first day of infusion. CONCLUSIONS Our small series, while confirming safety, failed to demonstrate a clinical benefit of autologous CIK cells given in its current form for AML and CML. Further manipulation of CIK cells to improve anti-leukemic potency and specificity, together with the preparation of patients to create a more conducive milieu for in vivo expansion and persistence of infused CIK cells, should be explored.

Chronic myeloid leukemia in the Asia-Pacific region: Current practice, challenges and opportunities in the targeted therapy era

Chronic myeloid leukemia (CML) management varies across Asia due to disparities in affluence and healthcare provision. We surveyed CML management practice at 33 hospitals in 14 countries/regions to identify treatment challenges and opportunities for harmonization. Patients were generally treated according to international guidelines; however, tyrosine kinase inhibitors (TKIs) and molecular monitoring are inaccessible to many patients not covered by national insurance or eligible for subsidized treatment. Late diagnosis and suboptimal monitoring, often due to cost and accessibility issues, are challenges. Priorities for Asia include: extending accessibility to TKIs; specialist laboratory monitoring; and enriching data to support regional CML management guidelines.

Relapse of Leukemia and Lymphoma after Marrow Transplant: A Review of Cases with Extramedullary Relapse

We review our cases of leukemia and lymphoma relapse after allogeneic marrow transplant and describe here a series of 10 patients with extramedullary (EM) relapse. In the 13 relapses in acute myeloid leukemia, 5 cases had EM involvement. There were 3 EM involvement out of 13 acute lymphoblastic leukemia relapses, one EM disease in 11 chronic myeloid leukemia relapses and one case of lymphoma with EM relapse. A common observation is that in some of these cases, EM relapse occurred in the presence of continuous marrow remission, In those cases with both marrow and EM involvement marrow remission could often be achieved and maintained temporarily while EM disease progressed despite chemotherapy or immunothera-peutic measures such as immunosuppressant withdrawal and donor lymphocyte infusion. Survival in partial remission after relapse could be prolonged in some cases but eventual death from progressive disease was often the case.

Use of the cytomegalovirus pp65 antigenemia assay for preemptive therapy In allogeneic hematopoietic stem cell transplantation : a real-world review

Abstract: Despite advances in surveillance strategies and antivirals, cytomegalovirus (CMV) infection continues to pose problems to patients receiving hematopoietic stem cell transplants (HSCTs). The bone marrow transplant (BMT) unit at the Singapore General Hospital embraced the preemptive strategy in late 2003. Although several studies have demonstrated its usefulness, we conducted this review to document CMV‐related events at our institution. Forty‐six patients underwent CMV surveillance using the CMV pp65 antigenemia (CMV Ag) assay from January 2004 to December 2005. Twenty‐seven patients had CMV infection, and 19 remained antigenemia‐negative. No differences were found between the 2 groups for the following potential risk factors for CMV infection: age, total number of co‐morbidities, duration of neutropenia after conditioning, baseline creatinine, type of conditioning regimen (conventional vs. reduced intensity), type of transplant (matched sibling vs. others), recipient CMV status, donor CMV status, and use of total body irradiation. Two patients received alemtuzumab; both developed CMV Ag. Twelve episodes of CMV infection occurred after the 100th post‐HSCT day. Two patients developed CMV disease. One of them could be considered a failure of the preemptive strategy, as she had CMV gastritis diagnosed on the same day that she became pp65‐positive. The other developed CMV disease despite prompt institution of ganciclovir, although she had multiple post‐HSCT complications requiring enhanced immunosuppression, as well as relapsed disease. One‐year disease‐free survival was 55.5% in those with CMV infection and 52.3% in those without infection. Survival was not affected by CMV infection.

Pre-transplant achievement of negativity in minimal residual disease and French–American–British L1 morphology predict superior outcome after allogeneic transplant for Philadelphia chromosome positive acute lymphoblastic leukemia: an analysis of Southeast Asian patients

Abstract To better understand predictive factors and improve the clinical outcome of allogeneic transplant for patients with Philadelphia positive acute lymphoblastic leukemia, we analyzed 67 Southeast Asian patients transplanted in our institutions. Multivariate analysis showed that disease status before transplant, year of transplant and, interestingly, French–American–British (FAB) subtype had a significant impact on overall survival (OS) and non-relapse mortality. Patients who were minimal residual disease (MRD) negative at transplant had a 3-year OS of 73% compared to those who were MRD positive (45%) and refractory (0%). The 3-year cumulative incidence of relapse was 18% and 36% for the MRD negative and positive groups, respectively. FAB L1 subtype had a significantly superior 3-year OS of 63% vs. 29% for L2 subtype. Pre-transplant use of a tyrosine kinase inhibitor significantly improved outcomes in univariate but not multivariate analysis, as it served to induce more patients into MRD negativity, which was the factor that directly improved transplant outcome.

Single center retrospective analysis of BU-based conditioning regimens in allogeneic transplantation

We performed a single institution retrospective analysis of 114 patients treated with BU-based pretransplant conditioning regimens. Oral BU was administered to 76 patients (total dose 16 mg/kg or 8 mg/kg) and i.v. BU to 38 others (total dose 12.8 mg/kg or 6.4 mg/kg). Either CY (n=74) or fludarabine (n=40) was given in combination with BU. Median age was 35 years in the oral BU group and 48.5 years with i.v. BU (P<0.001). OS and PFS rates at 3-years post HSCT were not different in patients who received either i.v. or oral BU (OS: 41.3 vs 44.0% (P=0.981); PFS: 52.7 vs 54.7% (P=0.526), respectively). The i.v. BU, however, was associated with a significantly shorter time to engraftment (13.5 days vs 16 days, respectively; P<0.001). There were no significant differences in survival or 100-day mortality for patients who received either CY or fludarabine, in combination with BU. After adjustment for confounders, multivariate analysis showed that age of transplant (P=0.002), donor type (sibling or unrelated; P=0.003), GVHD (P<0.05) and route of administration (P=0.023) were significant risk factors for OS. The i.v. BU used in an older age group yielded equivalent survival compared with oral BU used in a younger population.

Respiratory virus infection after allogeneic hematopoietic stem cell transplant in a tropical center: Predictive value of the immunodeficiency scoring index

Respiratory virus infection (RVI) is a prevalent infection in patients after allogeneic hematopoietic stem cell transplant (allo‐HSCT) and can result in significant morbidity and mortality. Ability to assess the potential severity of RVI is important in the management of such patients.

Long‐term renal outcome after allogeneic hemopoietic stem cell transplant: A comprehensive analysis of risk factors in an Asian patient population

Allogeneic hemopoietic stem cell transplantation (allo‐HSCT) poses a significant challenge to renal function due to multiple drug‐ and complication‐related renal toxicity. In this single‐center series of 216 adult Asian patients with a long and complete follow‐up, 41 developed chronic kidney disease (CKD) giving a cumulative incidence of 19.0% at 25 years (median follow‐up duration 7.84 years, range 2.0‐27.7 years), but only two of the 41 patients reached stage 4 CKD and another two required dialysis. In contrast, acute kidney injury occurred in most patients, where glomerular filtration rate (GFR) suffered a mean fall of 50 mL/min/1.73 m2 at 6 months post‐transplant compared with baseline. Suppression of renal function may last beyond 6 months but is potentially reversible, although not to baseline level in most patients. Analysis of a comprehensive range of 18 risk factors showed that older age, lower GFR at transplant, unrelated donor, diagnosis of AML, presence of diabetes mellitus at transplant, and duration of foscarnet use were significantly associated with CKD development, with the first three remaining as independent risks for CKD in multivariate analysis. Long‐term survival is not affected by renal function, being 78.6% as compared to 85.5% for patients with low vs normal GFR at 2 years, respectively.