Young-Ah Kang

Donor-Derived Natural Killer Cells Infused after Human Leukocyte Antigen–Haploidentical Hematopoietic Cell Transplantation: A Dose-Escalation Study

The doses of donor-derived natural killer (NK) cells that can be given safely after human leukocyte antigen (HLA)-haploidentical hematopoietic cell transplantation (HCT) remain to be defined. Forty-one patients (ages 17 to 75 years) with hematologic malignancy underwent HLA-haploidentical HCT after reduced-intensity conditioning containing busulfan, fludarabine, and antithymocyte globulin. Cell donors (ages 7 to 62 years) underwent growth factor-mobilized leukapheresis for 3 to 4 days. Cells collected on the first 2 to 3 days were used for HCT, whereas those collected on the last day were CD3-depleted and cultured into NK cells using human interleukins-15 and -21. These NK cells were then infused into patients twice at 2 and 3 weeks after HCT at an escalating doses of .2 × 10(8) cells/kg of body weight (3 patients), .5 × 10(8) cells/kg (3 patients), 1.0 × 10(8) cells/kg (8 patients), and ≥ 1.0 × 10(8) cells/kg or available cells (27 patients). At all dose levels, no acute toxicity was observed after NK cell infusion. After HLA-haploidentical HCT and subsequent donor NK cell infusion, when referenced to 31 historical patients who had undergone HLA-haploidentical HCT after the same conditioning regimen but without high-dose NK cell infusion, there was no significant difference in the cumulative incidences of major HCT outcomes, including engraftment (absolute neutrophil count ≥ 500/μL, 85% versus 87%), grade 2 to 4 acute graft-versus-host disease (GVHD, 17% versus 16%), moderate to severe chronic GVHD (15% versus 10%), and transplantation-related mortality (27% versus 19%). There was, however, a significant reduction in leukemia progression (74% to 46%), with post-transplantation NK cell infusion being an independent predictor for less leukemia progression (hazard ratio, .527). Our findings showed that, when given 2 to 3 weeks after HLA-haploidentical HCT, donor-derived NK cells were well tolerated at a median total dose of 2.0 × 10(8) cells/kg. In addition, they may decrease post-transplantation progression of acute leukemia.

C3435T polymorphism of the MDR1 gene is not associated with P-glycoprotein function of leukemic blasts and clinical outcome in patients with acute myeloid leukemia

We investigated the association between the MDR1 C3435T polymorphism and P-glycoprotein function of leukemic blasts as well as clinical outcomes in 200 patients with AML, excluding the M3 subtype. The CC, CT and TT genotype frequencies of the C3435T polymorphism among patients were 71, 93 and 36, respectively. The C3435T polymorphism genotypes did not have influence on the P-glycoprotein function of leukemic blasts. Complete remission rates and overall, relapse-free and event-free survival rates were not significantly different among the C3435T polymorphism genotypes. In conclusion, the MDR1 C3435T polymorphism does not appear to have significant clinical implications in AML.

Hematopoietic cell transplantation from an HLA-mismatched familial donor is feasible without ex vivo-T cell depletion after reduced-intensity conditioning with busulfan, fludarabine, and antithymocyte globulin.

To extend the use of allogeneic hematopoietic cell transplantation (HCT) to patients without an HLA-matched donor, we investigated HCT from a related donor with 1 fully mismatched HLA-haplotype after conditioning with busulfan in reduced-dose, fludarabine, and antithymocyte globulin. Hematopoietic cells were collected from the donors via leukapheresis after mobilization and infused without further manipulation. Cyclosporin and methotrexate were administered for graft-versus-host disease (GVHD) prophylaxis. Posttransplant engraftment, GVHD, and transplantation-related mortality (TRM) were recorded. Thirty-one patients (age range: 16-69 years) with high-risk acute leukemia/myelodysplastic syndrome (n = 25) or bone marrow failure (n = 6) were enrolled. The donors were either mothers (n = 14), offspring (n = 9), or siblings (n = 8) of these patients. Excluding 3 patients who died or relapsed with leukemia within 3 weeks after HCT, all the remaining 28 patients engrafted with neutrophils (>500/microL) at a median of 16.5 days. Twenty-two of 24 evaluated patients achieved complete donor chimerism (> or =95%) 2 weeks after HCT and none experienced graft failure subsequently. The cumulative incidences of grade 2-4 acute GVHD (aGVHD) and moderate-severe chronic GVHD (cGVHD) were 19% (95% confidence interval [CI], 9%-40%) and 20% (95% CI, 10%-41%), respectively. After a median follow-up of 18.2 months (range: 6.3-52.1), 18 patients remained alive (53%). Four patients died without recurrence/progression of underlying diseases giving a TRM of 13% (95% CI, 5%-33%). HCT from an HLA-mismatched family member is feasible without ex vivo T cell depletion when reduced-intensity conditioning containing anti-hymocyte globulin is performed.

Clinical effect of reduced-intensity conditioning regimen containing antithymocyte globulin for hematopoietic cell transplantation from unrelated-donors†‡

The impact of reduced‐intensity conditioning (RIC) on the outcomes of hematopoietic cell transplantation (HCT) from unrelated ‐donors (UD) remains to be determined. We therefore assessed 128 patients, aged 16 to 66 years, with acute leukemia (n = 105) or myelodysplastic syndrome (n = 23) in a UD‐HCT trial using RIC with busulfan, fludarabine, and antithymocyte globulin. Patients were transplanted with unmanipulated bone marrow (BM, n = 41) or mobilized peripheral blood mononuclear cells (M‐PB, n = 87) and received cyclosporine and methotrexate for graft‐versus‐host disease (GVHD) prophylaxis. After a median follow‐up of 26.7 months (range, 5.9−70.7 months) in surviving patients, 19 patients had died without progression/recurrence of underlying disease, giving a cumulative incidence of transplantation‐related mortality (TRM) of 17% (95% confidence interval, 11%–27%; 1‐year TRM, 14%). Graft failure (n = 7) and infections (n = 5) were the most common causes of TRM. Only three patients died due to GVHD (acute, one; chronic, two). Graft failure, which occurred in eight patients, showed a significant correlation with graft source (BM, 6/41 vs. M‐PB, 2/87; P = 0.009). Donor‐patient HLA‐disparity did not correlate with GVHD, 1‐year TRM, and graft failure. RIC containing antithymocyte globulin led to decreased GVHD‐associated, as well as overall, TRM after UD‐HCT. This trial is registered at www.clinicaltrials.gov as NCT00627666. Am. J. Hematol. 86:399–405,2011.

Differences of cytomegalovirus diseases between kidney and hematopoietic stem cell transplant recipients during preemptive therapy

Background/Aims: Cytomegalovirus (CMV) surveillance and preemptive therapy is a widely-used strategy for preventing CMV disease in transplant recipients. However, there are limited data on the incidence and patterns of CMV disease during the preemptive period. Thus, we investigated the incidence and pattern of tissue-invasive CMV disease in CMV seropositive kidney transplantation (KT) and hematopoietic stem cell transplantation (HCT) recipients during preemptive therapy. Methods: We prospectively identified patients with tissue-invasive CMV disease among 664 KT (90%) and 496 HCT (96%) recipients who were D+/R+ (both donor and recipient seropositive) during a 4-year period. Results: The incidence rates of CMV disease were 4.1/100 person-years (4%, 27/664) in KT recipients and 5.0/100 person-years (4%, 21/496) in HCT recipients. Twenty-six (96%) of the KT recipients with CMV disease had gastrointestinal CMV, whereas 17 (81%) of the HCT recipients had gastrointestinal CMV and 4 (19%) had CMV retinitis. Thus, CMV retinitis was more common among HCT recipients (p = 0.03). All 27 KT recipients with CMV disease suffered abrupt onset of CMV disease before or during preemptive therapy; 10 (48%) of the 21 HCT recipients with CMV disease were also classified in this way but the other 11 (52%) were classified as CMV disease following successful ganciclovir preemptive therapy (p < 0.001). Conclusions: The incidence of CMV disease was about 4% in both KT and HCT recipients during preemptive therapy. However, CMV retinitis and CMV disease as a relapsed infection were more frequently found among HCT recipients.

Clinical significance of GSTM1 and GSTT1 polymorphisms in younger patients with acute myeloid leukemia of intermediate-risk cytogenetics

We investigated the association between GSTM1 or GSTT1 polymorphisms and clinical outcomes in 133 younger patients with AML of intermediate-risk cytogenetics. Clinical outcomes were not significantly different among the GSTM1 polymorphism genotypes, whereas cumulative incidence of relapse (CIR) was significantly lower and event-free survival (EFS) was significantly higher in patients with the GSTT1-present genotype compared with those with the GSTT1-null genotype (CIR at 5 year, 28.9% vs. 44.6%, P=0.018; EFS at 5 year, 51.4% vs. 34.1%, P=0.029). Our results suggest that GSTT1 gene polymorphism has significant clinical implications in younger patients with AML of intermediate-risk cytogenetics.

Single-dose mitoxantrone in combination with continuous infusion intermediate-dose cytarabine plus etoposide for treatment of refractory or early relapsed acute myeloid leukemia

This prospective phase II clinical trial evaluated the effects of single-dose mitoxantrone (36 mg/m2 on day 1) in combination with continuous infusion intermediate-dose cytarabine plus etoposide in 25 patients with refractory or early relapsed acute myeloid leukemia (AML). We compared the results of our current study with those of a previous phase II trial, which had the same eligibility criteria and chemotherapy schedule except that a conventional divided dose of mitoxantrone (12 mg/m2 on days 1-3) was used. The complete remission (CR) rate was significantly lower with the single-dose mitoxantrone regimen than with the divided-dose regimen (24.0% vs. 51.5%; P=0.034), mainly owing to an increased incidence of hypoplastic deaths. CR duration and overall survival were not significantly different between the two regimens. In conclusion, single-dose mitoxantrone was inferior to conventional divided-dose mitoxantrone for treatment of refractory or early relapsed AML in terms of CR rate.

Diagnostic usefulness of dynamic changes of CMV-specific T-cell responses in predicting CMV infections in HCT recipients.

BACKGROUND CMV-specific cell mediated immune responses before and after hematopoietic stem cell transplantation (HCT) can categorize patients as at high or low risk of CMV development. OBJECTIVES We evaluated the usefulness of the CMV-specific T-cell ELISPOT assay for predicting the development of CMV infections after HCT in recipients with donor-positive and recipient-positive CMV serology (D+/R+ ). STUDY DESIGN CMV pp65 and IE1-specific ELISPOT assays were performed before HCT (D0), and at 30 (D30) and 90 (D90) days after HCT. RESULTS Of the 84 HCT recipients with D+/R+, 42 (50%) developed≥1 episode of CMV infection. Thirty-nine (64%) of 61 patients with Δ(D30-D0) pp65<42 developed CMV infections compared with 3 (14%) of 21 patients with Δ(D30-D0) pp65≥42 (P<0.001). Twenty-three (74%) of 31 patients with Δ(D30-D0) IE1<-4 developed CMV infections compared with 19 (37%) of 51 patients with Δ(D30-D0) IE1≥-4 (P=0.001). pp65 Δ(D30-D0) ≥42 had 93% sensitivity for ruling out subsequent CMV infection, and pp65 Δ(D30-D0)<42 followed by Δ(D30-D0) IE1<-4 had 100% specificity for ruling in the subsequent CMV infection. In addition, 10 (53%) of 19 patients with Δ(D90-D30) pp65<23 had relapsing CMV infections, compared with 3 (15%) of 20 patients with Δ(D90-D30) pp65≥23 (P=0.02). The sensitivity and specificity of Δ(D90-D30) pp65 were 77% (95% CI 50-92) and 65% (95% CI, 46-81). CONCLUSION Dynamic change in the CMV-specific ELISPOT assay before versus after HCT appears to predict the subsequent development of CMV infection and relapsing CMV infection.

Comparison of anthracyclines used for induction chemotherapy in patients with FLT3 -ITD-mutated acute myeloid leukemia

This retrospective analysis compared anthracyclines (as part of an induction regimen) in 128 newly diagnosed FLT3-ITD-mutated AML patients. Induction regimens comprised high-dose daunorubicin (HD-DN; 90 mg/m2/d × 3d; n = 44), standard-dose daunorubicin (SD-DN; 45 mg/m2/d × 3d; n = 51), or idarubicin (IDA; 12 mg/m2/d × 3d; n = 33) in combination with cytarabine (100-200 mg/m2/d × 7d). Fifty-three patients showing persistent leukemia on interim bone marrow examination received a second course of induction chemotherapy comprising 2 days of daunorubicin (45 mg/m2/d) or IDA (8 or 12 mg/m2/d) in addition to 5 days of cytarabine. Complete remission (CR) rates were 77.3%, 56.9%, and 69.7% for HD-DN, SD-DN, and IDA, respectively (P = 0.101; HD-DN vs. SD-DN, P = 0.036; HD-DN vs. IDA, P = 0.453; IDA vs. SD-DN, P = 0.237). The HD-DN showed higher overall survival (OS) and event-free survival (EFS) than SD-DN and IDA: the differences between HD-DN and SD-DN (P = 0.009 for OS and P = 0.010 for EFS) were statistically significant. Results of in vitro studies using FLT3-ITD-mutated cell lines supported these findings. In conclusion, HD-DN improved the CR rate, OS, and EFS of FLT3-ITD-mutated AML patients. HD-DN also tended to yield better outcomes than IDA, though the difference was not significant. The superiority of HD-DN over IDA should be confirmed in future studies.

Allogeneic hematopoietic cell transplantation for lymphoma: baseline and posttransplant prognostic factors

Abstract The present study aimed to investigate baseline and posttransplant prognostic factors for allogeneic hematopoietic cell transplantation (HCT) in 61 lymphoma patients. The 5-year probabilities of overall survival (OS), non-relapse mortality (NRM), progression-free survival (PFS), and event-free survival (EFS) were 31.1%, 28.8%, 38.8%, and 23.2%, respectively. Multivariate analysis demonstrated that the International Prognostic Index risk at HCT was a significantly independent prognostic factor for OS, NRM, PFS, and EFS, and chemosensitivity was a prognostic factor for OS, NRM, and EFS. The occurrence of chronic graft-versus-host disease (GVHD) was significantly associated with higher OS, but it was not with PFS or EFS. Various parameters of immune reconstitution at 1 month after transplantation were associated with clinical outcomes in different ways. Our study results might be helpful in selecting appropriate patients or adopting effective posttransplant treatment strategies, eventually leading to an improvement in outcomes after allogeneic HCT for lymphoma.