Early relapse after autologous hematopoietic cell transplantation remains a poor prognostic factor in multiple myeloma but outcomes have improved over time.

Duration of initial disease response remains a strong prognostic factor in multiple myeloma (MM) particularly for upfront autologous hematopoietic cell transplant (AHCT) recipients. We hypothesized that new drug classes and combinations employed prior to AHCT as well as after post-AHCT relapse may have changed the natural history of MM in this population. We analyzed the Center for International Blood and Marrow Transplant Research database to track overall survival (OS) of MM patients receiving single AHCT within 12 months after diagnosis (N=3256) and relapsing early post-AHCT (<24 months), and to identify factors predicting for early vs late relapses (24-48 months post-AHCT). Over three periods (2001-2004, 2005-2008, 2009-2013), patient characteristics were balanced except for lower proportion of Stage III, higher likelihood of one induction therapy with novel triplets and higher rates of planned post-AHCT maintenance over time. The proportion of patients relapsing early was stable over time at 35-38%. Factors reducing risk of early relapse included lower stage, chemosensitivity, transplant after 2008 and post-AHCT maintenance. Shorter post-relapse OS was associated with early relapse, IgA MM, Karnofsky <90, stage III, >1 line of induction and lack of maintenance. Post-AHCT early relapse remains a poor prognostic factor, even though outcomes have improved over time.

Autologous hematopoietic cell transplantation for multiple myeloma patients with renal insufficiency: a center for international blood and marrow transplant research analysis.

Autologous hematopoietic cell transplantation (AHCT) in multiple myeloma (MM) patients with renal insufficiency (RI) is controversial. Patients who underwent AHCT for MM between 2008 and 2013 were identified (N=1492) and grouped as normal/mild (⩾60 mL/min), N=1240, moderate (30-59), N=185 and severe RI (<30), N=67 based on Modification of Diet in Renal Disease. Multivariate analyses of non-relapse mortality (NRM), relapse, PFS and overall survival (OS) were performed. Of the 67 patients with severe RI, 35 were on dialysis prior to AHCT. Patients received melphalan 200 mg/m2 (Mel 200) in 92% (normal/mild), 75% (moderate) and 33% (severe) RI; remainder received 140 mg/m2 (Mel 140). Thirty four of 35 patients with severe RI achieved post-AHCT dialysis independence. The 5-year PFS for normal, moderate and severe RI was 35 (95% CI, 31-38)%, 40 (31-49)% and 27 (15-40)%, respectively, (P=0.42); 5-year OS for normal, moderate and severe RI was 68 (65-71)%, 68 (60-76)% and 60 (46-74)%, respectively, (P=0.69). With moderate RI, 5-year PFS for high-dose melphalan 140 mg/m2 was 18 (6-35)% and for Mel 200 was 46 (36-57)% (P=0.009). With severe RI, 5-year PFS Mel 140 was 25 (11-41) % and for Mel 200 was 32 (11-58)% (P=0.37). We conclude that AHCT is safe and effective in patients with MM with RI.

Predictors of overall survival among patients treated with sirolimus/tacrolimus vs methotrexate/tacrolimus for GvHD prevention.

Sirolimus (SIR)/tacrolimus (TAC) is an alternative to methotrexate (MTX)/TAC. However, rational selection among these GvHD prophylaxis approaches to optimize survival of individual patients is not possible based on current evidence. We compared SIR/TAC (n=293) to MTX/TAC (n=414). The primary objective was to identify unique predictors of overall survival (OS). Secondary objective was to compare acute and chronic GvHD, relapse, non-relapse mortality, thrombotic microangiopathy (TMA), hepatic veno-occlusive disease (VOD/SOS), and acute kidney injury. Day 100 grades II-IV acute GvHD was significantly reduced in SIR/TAC vs MTX/TAC group (63 vs 73%, P=0.02). An interaction between GvHD prophylaxis groups and comorbidity index (hematopoietic cell transplantation (HCT)-CI) significantly impacted OS. Patients with HCT-CI⩾4 had significantly worse OS with MTX/TAC (HR 1.86, 95% CI 1.14-3.04, P=0.01) while no such effect was seen for SIR/TAC (HR 0.78, 95% CI 0.48-1.26, P=0.31). Other end points did not significantly differ between groups except TMA and VOD/SOS were increased in the SIR/TAC group, but excess death from these complications was not observed. We conclude, GvHD prophylaxis approach of SIR/TAC is associated with reduced grades II-IV acute GvHD, comparable toxicity profile to MTX/TAC, and improved OS among patients with HCT-CI⩾4.

GvHD after umbilical cord blood transplantation for acute leukemia: an analysis of risk factors and effect on outcomes.

Using the Center for International Blood and Marrow Transplant Research (CIBMTR) registry, we analyzed 1404 umbilical cord blood transplantation (UCBT) patients (single (<18 years)=810, double (⩾18 years)=594) with acute leukemia to define the incidence of acute GvHD (aGvHD) and chronic GvHD (cGvHD), analyze clinical risk factors and investigate outcomes. After single UCBT, 100-day incidence of grade II-IV aGvHD was 39% (95% confidence interval (CI), 36-43%), grade III-IV aGvHD was 18% (95% CI, 15-20%) and 1-year cGvHD was 27% (95% CI, 24-30%). After double UCBT, 100-day incidence of grade II-IV aGvHD was 45% (95% CI, 41-49%), grade III-IV aGvHD was 22% (95% CI, 19-26%) and 1-year cGvHD was 26% (95% CI, 22-29%). For single UCBT, multivariate analysis showed that absence of antithymocyte globulin (ATG) was associated with aGvHD, whereas prior aGvHD was associated with cGvHD. For double UCBT, absence of ATG and myeloablative conditioning were associated with aGvHD, whereas prior aGvHD predicted for cGvHD. Grade III-IV aGvHD led to worse survival, whereas cGvHD had no significant effect on disease-free or overall survival. GvHD is prevalent after UCBT with severe aGvHD leading to higher mortality. Future research in UCBT should prioritize prevention of GvHD.

Contribution of chemotherapy mobilization to disease control in multiple myeloma treated with autologous hematopoietic cell transplantation.

In patients with multiple myeloma (MM) undergoing autologous hematopoietic cell transplantation (auto-HCT), peripheral blood progenitor cells may be collected following mobilization with growth factor alone (GF) or cytotoxic chemotherapy plus GF (CC+GF). It is uncertain whether the method of mobilization affects post-transplant outcomes. We compared these mobilization strategies in a retrospective analysis of 968 patients with MM from the Center for International Blood and Marrow Transplant Research database who received an auto-HCT in the US and Canada between 2007 and 2012. The kinetics of neutrophil engraftment (⩾0.5 × 10(9)/L) was similar between groups (13 vs 13 days, P=0.69) while platelet engraftment (⩾20 × 10(9)/L) was slightly faster with CC+GF (19 vs 18 days, P=0.006). Adjusted 3-year PFS was 43% (95% confidence interval (CI) 38-48) in GF and 40% (95% CI 35-45) in CC+GF, P=0.33. Adjusted 3-year OS was 82% (95% CI 78-86) vs 80% (95% CI 75-84), P=0.43 and adjusted 5-year OS was 62% (95% CI 54-68) vs 60% (95% CI 52-67), P=0.76, for GF and CC+GF, respectively. We conclude that MM patients undergoing auto-HCT have similar outcomes irrespective of the method of mobilization and found no evidence that the addition of chemotherapy to mobilization contributes to disease control.

A prognostic model predicting autologous transplantation outcomes in children, adolescents and young adults with Hodgkin lymphoma.

Autologous hematopoietic cell transplantation (AutoHCT) is a potentially curative treatment modality for relapsed/refractory Hodgkin lymphoma (HL). However, no large studies have evaluated pretransplant factors predictive of outcomes of AutoHCT in children, adolescents and young adults (CAYA, age <30 years). In a retrospective study, we analyzed 606 CAYA patients (median age 23 years) with relapsed/refractory HL who underwent AutoHCT between 1995 and 2010. The probabilities of PFS at 1, 5 and 10 years were 66% (95% confidence interval (CI): 62-70), 52% (95% CI: 48-57) and 47% (95% CI: 42-51), respectively. Multivariate analysis for PFS demonstrated that at the time of AutoHCT patients with Karnofsky/Lansky score ⩾90, no extranodal involvement and chemosensitive disease had significantly improved PFS. Patients with time from diagnosis to first relapse of <1 year had a significantly inferior PFS. A prognostic model for PFS was developed that stratified patients into low-, intermediate- and high-risk groups, predicting for 5-year PFS probabilities of 72% (95% CI: 64-80), 53% (95% CI: 47-59) and 23% (95% CI: 9-36), respectively. This large study identifies a group of CAYA patients with relapsed/refractory HL who are at high risk of progression after AutoHCT. Such patients should be targeted for novel therapeutic and/or maintenance approaches post-AutoHCT.

Allogeneic hematopoietic cell transplant for AML: no impact of pre-transplant extramedullary disease on outcome.

The impact of extramedullary disease (EMD) in AML on the outcomes of allogeneic hematopoietic cell transplantation (alloHCT) is unknown. Using data from the Center for International Blood and Marrow Transplant Research, we compared the outcomes of patients who had EMD of AML at any time before transplant, with a cohort of AML patients without EMD. We reviewed data from 9797 AML patients including 814 with EMD from 310 reporting centers and 44 different countries, who underwent alloHCT between and 1995 and 2010. The primary outcome was overall survival (OS) after alloHCT. Secondary outcomes included leukemia-free survival (LFS), relapse rate and treatment-related mortality (TRM). In a multivariate analysis, the presence of EMD did not affect either OS (hazard ratio 1.00, 95% confidence interval (CI) 0.91-1.09), LFS (0.98, 0.89-1.09), TRM (relative risk 0.92, 95% CI 0.80-1.16, P=0.23) or relapse (relative risk=1.03, 95% CI, 0.92-1.16; P=0.62). Furthermore, the outcome of patients with EMD was not influenced by the location, timing of EMD, or intensity of conditioning regimen. The presence of EMD in AML does not affect transplant outcomes and should not be viewed as an independent adverse prognostic feature.

Comparison of 1-day vs 2-day dosing of high-dose melphalan followed by autologous hematopoietic cell transplantation in patients with multiple myeloma.

High-dose melphalan at 200 mg/m(2) can be administered in 1 day or over 2 consecutive days before autologous hematopoietic cell transplantation (HCT) for multiple myeloma (MM). Limited data exist on the comparison of the two dosing schedules. A retrospective study of 278 consecutive MM patients receiving high-dose melphalan from January 2010 to December 2012 was conducted. Objectives were to compare the length of hospitalization, toxicity profile, response rates, PFS and OS. One hundred and eighty five patients received 2-day dosing and 93 received 1-day dosing. The two end points of the 95% confidence interval (CI) for the difference did not exceed the preselected margin, therefore the length of hospitalization was considered equivalent. No significant differences were found for response rates, PFS and OS.  The toxicity profile was similar with the exception of more frequent ⩾grade 3 oral mucositis in the 2-day group (13.5% vs 5.4%; odds ratio 3.07 (95% CI:1.11-8.48); P=0.03). High-dose melphalan, given either in 1 day or over 2 days, produced comparable treatment outcomes except for increased grade 3/4 mucositis in the 2-day regimen. One-day dosing could shorten the hospital stay by 1 day and may allow better resource utilization.

Pharmacokinetically-targeted BU and fludarabine as conditioning before allogeneic hematopoietic cell transplantation for adults with ALL in first remission.

Allogeneic hematopoietic cell transplantation offers improved survival in patients with ALL, but with regimens containing TBI, the nonrelapse mortality is 20-40%. Efforts to lessen transplant toxicities by reducing conditioning regimen intensity have led to increased relapse risk. Therefore, there is a need for less toxic regimens that maintain an anti-leukemia effect. We report here a retrospective review of 65 patients with ALL in first remission receiving grafts from allogeneic donors after fludarabine 40 mg/m(2)/day for 4 days and i.v. BU targeted to a median daily area under the concentration-time curve below 6000 µmoles min/L. At 2 years after transplantation, OS was 65% (95% confidence interval (CI): 52-77%), relapse-free survival was 61% (95% CI: 48-73%), cumulative incidence of relapse was 26% (95% CI: 17-39%) and cumulative incidence of nonrelapse mortality was 14% (95% CI: 8-26%). Age over 35 years, Ph chromosome positivity and minimal residual disease at transplant did not adversely affect outcomes. Pharmacokinetically targeted BU and fludarabine can provide intensive pre-transplant conditioning for adults with ALL in first remission, with promising relapse-free and OS rates.

Allogeneic hematopoietic cell transplantation for consolidation of VGPR or CR for newly diagnosed multiple myeloma.

Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative approach in patients with multiple myeloma, but its use for consolidation of first remission has not yet been fully explored. Twenty-two myeloma patients with very good partial response (VGPR) or CR received allogeneic peripheral blood grafts as consolidation from HLA-matched donors between 2007 and 2012. Conditioning regimens were fludarabine (30 mg/m(2) i.v. if with bortezomib and 40 mg/m(2) i.v. when without bortezomib, × 4 days) plus melphalan (70 mg/m(2) intravenously × 2 days) with (n=13) or without (n=9) bortezomib (1.3 mg/m(2)). The cumulative incidence of grades II - IV acute GVHD at day 100 was 45% (95% CI: 24-65%) and moderate-to-severe chronic GVHD at 2 years was 46% (95% CI: 19-69%). With a median follow-up of 18 (range, 2-61) months, the 2-year PFS estimate is 74.8% (95% CI: 45-90%), which compares favorably with the 52% (95% CI: 35-66%) after autologous HCT for similar patients (a median follow-up of 30 (range, 9-55) months). We are conducting a phase 2 study to assess the efficacy of allogeneic HCT as post-remission therapy.

Race/ethnicity affects the probability of finding an HLA-A, -B, -C and -DRB1 allele-matched unrelated donor and likelihood of subsequent transplant utilization.

Factors relevant to finding a suitable unrelated donor and barriers to effective transplant utilization are incompletely understood. Among a consecutive series of unrelated searches (n=531), an 8/8 HLA-A, -B, -C and -DRB1-matched unrelated donor was available for 289 (54%) patients, 7/8 for 159 (30%) and no donor for 83 (16%). Patients of Caucasian race (P<0.0001) were more likely to find a donor. Younger age (P=0.01), Caucasian race (P=0.03), lower CIBMTR (Center for International Blood and Marrow Transplantation Research) risk (P=0.005), and 8/8 HLA matching (P=0.005) were associated with higher odds of reaching hematopoietic cell transplantation (HCT). In a univariate analysis of OS, finding a donor was associated with hazard ratio (HR) of 0.85 (95% CI 0.63-1.2), P=0.31. Karnofsky performance status (KPS) accounted for interaction between having a donor and survival. Patients with KPS 90-100 and a donor had significantly reduced hazard for death (HR 0.59, 95% CI 0.38-0.90, P=0.02). These data provide estimates of the probability to find an unrelated donor in the era of high-resolution HLA typing, and identify potentially modifiable barriers to reaching HCT. Further efforts are needed to enhance effective donor identification and transplant utilization, particularly in non-Caucasian ethnic groups.

Role of reduced intensity conditioning in allogeneic hematopoietic cell transplantation for patients with multiple myeloma.

High-dose chemotherapy followed by autologous hematopoietic cell transplantation continues to play an integral role in the treatment strategy in patients with newly diagnosed multiple myeloma. Incorporation of newer potent anti-myeloma agents has further improved outcomes. However, disease relapse or progression remains a challenge after autologous transplantation. Allogeneic hematopoietic cell transplantation remains the only potentially curative modality for some patients due in part to graft-versus-myeloma effect. High transplant-related mortality, in the range of 30% to 40%, previously seen with myeloablative conditioning regimens, including total body irradiation plus cyclophosphamide has been significantly reduced by introducing less ablative preparative regimens, so called reduced-intensity conditioning. Cumulative evidence suggests encouraging prospects for allogeneic transplantation through improved outcomes of myeloma patients (overall survival exceeding 70% at 2 years in some studies); however, which patient population would benefit most from this treatment remains to be defined. newer strategies to augment graft-versus-myeloma effect and minimize post transplant toxicities are in need of further improvement in patients with myeloma.

The relevance of an elevation in the plasma vasopressin levels to the pathogenesis of Meniere's attack.

An elevation of plasma vasopressin levels has been frequently observed in Meniere's disease patients. However, little is known regarding the mechanism behind this elevation. The plasma vasopressin levels and plasma osmolality were therefore determined in 18 diagnosed Meniere's disease patients and 20 patients with other types of vertigo, who required admission for severe vertigo attacks. All participants were given questionnaires regarding their clinical and psychological status, including their stress levels and depression status, to evaluate environmental stress events. The plasma vasopressin levels of Meniere's disease patients in the acute phase (4.1 +/- 1.37 pg/ml) were significantly higher compared with with those of other vertigo patients in the acute phase (2.1 +/- 0.41 pg/ml) (P < 0.01). The average plasma osmolality of the Meniere's disease group was higher than that of the other vertigo patients group (P < 0.05). No significant difference in reported stress levels, depression status and prevalence of primary headache between the groups was observed. The plasma vasopressin showed no significant correlation with the patients' clinical data (occurrence of emesis or nausea, prevalence of primary headache, depression status and stress). No correlation between the plasma vasopressin and the plasma osmolarity was observed in the Meniere's disease group. These results suggest that the elevation of plasma vasopressin in the acute phase of Meniere's disease is therefore related to the pathogenesis of Meniere's attacks, and the results obtained may provide helpful information for distinguishing between Meniere's disease and other various inner ear diseases.

Effect of fluvoxamine on the pharmacokinetics of mexiletine in healthy Japanese men.

BACKGROUND AND OBJECTIVES: Fluvoxamine, a selective serotonin reuptake inhibitor, is known to inhibit several hepatic cytochrome P450 (CYP) isozymes, in particular CYP1A2. Mexiletine is mainly catalyzed by CYP2D6 and partially catalyzed by CYP1A2. Our objective was to study the potential pharmacokinetic interaction between fluvoxamine and mexiletine. METHODS: A randomized crossover design with two phases was used. A 7-day washout period separated the two treatment conditions. In the one phase, 6 healthy Japanese men received an oral dose of 200 mg of mexiletine alone (study 1); in the other phase, the men received fluvoxamine (50 mg twice a day) for 7 days, and on the eighth day they received oral mexiletine (200 mg) and fluvoxamine concomitantly (study 2). The concentrations of mexiletine were measured with HPLC. RESULTS: The area under the concentration-time curve and serum peak concentration of mexiletine in study 2 were significantly increased compared with those in study 1 (10.4 +/- 4.85 versus 6.70 +/- 3.21 microg x h/mL, P =.006 and 0.623 +/- 0.133 versus 0.536 +/- 0.164 microg/mL, P =.008, respectively). CONCLUSION: The effect of fluvoxamine on the mexiletine disposition is comparatively large, and when mexiletine and fluvoxamine are coadministered careful monitoring of mexiletine is needed.