Allogeneic hematopoietic cell transplantation for advanced polycythemia vera and essential thrombocythemia.

Allogeneic hematopoietic cell transplantation (HCT) is curative for selected patients with advanced essential thrombocythemia (ET) or polycythemia vera (PV). From 1990 to 2007, 75 patients with ET (median age 49 years) and 42 patients with PV (median age 53 years) underwent transplantations at the Fred Hutchinson Cancer Research Center (FHCRC; n = 43) or at other Center for International Blood and Marrow Transplant Research (CIBMTR) centers (n = 74). Thirty-eight percent of the patients had splenomegaly and 28% had a prior splenectomy. Most patients (69% for ET and 67% for PV) received a myeloablative (MA) conditioning regimen. Cumulative incidence of neutrophil engraftment at 28 days was 88% for ET patients and 90% for PV patients. Acute graft-versus-host disease (aGVHD) grades II to IV occurred in 57% and 50% of ET and PV patients, respectively. The 1-year treatment-related mortality (TRM) was 27% for ET and 22% for PV. The 5-year cumulative incidence of relapse was 13% for ET and 30% for PV. Five-year survival/progression-free survival (PFS) was 55%/47% and 71%/48% for ET and PV, respectively. Patients without splenomegaly had faster neutrophil and platelet engraftment, but there were no differences in TRM, survival, or PFS. Presence of myelofibrosis (MF) did not affect engraftment or TRM. Over 45% of the patients who undergo transplantations for ET and PV experience long-term PFS.

Reducing the risk for transplantation-related mortality after allogeneic hematopoietic cell transplantation: how much progress has been made?

PURPOSE: Transplantation-related mortality (TRM) is a major barrier to the success of allogeneic hematopoietic cell transplantation (HCT). PATIENTS AND METHODS: We assessed changes in the incidence of TRM and overall survival from 1985 through 2004 in 5,972 patients younger than age 50 years who received myeloablative conditioning and HCT for acute myeloid leukemia (AML) in first complete remission (CR1) or second complete remission (CR2). RESULTS: Among HLA-matched sibling donor transplantation recipients, the relative risks (RRs) for TRM were 0.5 and 0.3 for 2000 to 2004 compared with those for 1985 to 1989 in patients in CR1 and CR2, respectively (P < .001). The RRs for all causes of mortality in the latter period were 0.73 (P = .001) and 0.60 (P = .005) for the CR1 and CR2 groups, respectively. Among unrelated donor transplantation recipients, the RRs for TRM were 0.73 (P = .095) and 0.58 (P < .001) for 2000 to 2004 compared with those in 1990 to 1994 in the CR1 and CR2 groups, respectively. Reductions in mortality were observed in the CR2 group (RR, 0.74; P = .03) but not in the CR1 group. CONCLUSION: Our results suggest that innovations in transplantation care since the 1980s and 1990s have reduced the risk of TRM in patients undergoing allogeneic HCT for AML and that this reduction has been accompanied by improvements in overall survival.

Impact of prior imatinib mesylate on the outcome of hematopoietic cell transplantation for chronic myeloid leukemia.

Imatinib mesylate (IM, Gleevec) has largely supplanted allogeneic hematopoietic cell transplantation (HCT) as first line therapy for chronic myeloid leukemia (CML). Nevertheless, many people with CML eventually undergo HCT, raising the question of whether prior IM therapy impacts HCT success. Data from the Center for International Blood and Marrow Transplant Research on 409 subjects treated with IM before HCT (IM(+)) and 900 subjects who did not receive IM before HCT (IM(-)) were analyzed. Among patients in first chronic phase, IM therapy before HCT was associated with better survival but no statistically significant differences in treatment-related mortality, relapse, and leukemia-free survival. Better HLA-matched donors, use of bone marrow, and transplantation within one year of diagnosis were also associated with better survival. A matched-pairs analysis was performed and confirmed a higher survival rate among first chronic phase patients receiving IM. Among patients transplanted with advanced CML, use of IM before HCT was not associated with treatment-related mortality, relapse, leukemia-free survival, or survival. Acute graft-versus-host disease rates were similar between IM(+) and IM(-) groups regardless of leukemia phase. These results should be reassuring to patients receiving IM before HCT.

A phase 1 multidose study of SGN-30 immunotherapy in patients with refractory or recurrent CD30+ hematologic malignancies.

Phase 1 testing of SGN-30, a chimeric monoclonal antibody for the treatment of CD30(+) malignancies, was conducted in a multicenter study. To explore the safety profile and establish the maximum tolerated dose (MTD), 24 patients with refractory or relapsed Hodgkin lymphoma or CD30(+) non-Hodgkin lymphoma received 6 weekly doses of intravenous SGN-30 at 4 dose levels (2, 4, 8, or 12 mg/kg). Serum concentrations of SGN-30 rose rapidly and were dose dependent. Adverse events were mild, with nausea, fatigue, and fever attributed to study treatment. One episode of hypersensitivity rash was reported. The MTD was not reached. Serious adverse events included herpes zoster (n = 2), influenza, and pneumonia. One patient with cutaneous anaplastic large cell lymphoma (8 mg/kg) achieved a complete response. Six patients, of whom 4 had Hodgkin lymphoma, achieved stable disease with durations ranging from 6 to 16 months. The pharmacokinetic profile of SGN-30 showed a biphasic disposition, and estimated half-lives ranging between 1 to 3 weeks. The 6 weekly infusions of SGN-30 resulted in approximately 2- to 3-fold accumulation in serum exposures consistently across the dose range. These results demonstrate that weekly administration of SGN-30 is safe and has modest clinical activity in patients with CD30(+) tumors. This trial is registered at http://www.ClinicalTrials.gov as no. NCT00051597.

Improved outcomes in intermediate- and high-risk aggressive non-Hodgkin lymphoma after autologous hematopoietic stem cell transplantation substituting intravenous for oral busulfan in a busulfan, cyclophosphamide, and etoposide preparative regimen.

Forty-nine patients with intermediate- and high-risk aggressive non-Hodgkin lymphoma underwent autologous hematopoietic stem cell transplantation (autoHSCT) using the regimen of busulfan (Bu), cyclophosphamide (Cy), and etoposide (E) that was originally developed for allogeneic HSCT. Eighteen patients treated before 1999 received Cy 2.5 g/m2 on days -3 to -2 and E 1800 mg/m2 on day -3 after oral (PO) administration of Bu 1 mg/kg every 6 hours x 4 days for a total of 16 doses beginning on day -7. After April 1999, 31 patients similar in all pretransplantation risk assessments received the same regimen except that intravenous (IV) Bu was substituted for PO Bu and pharmacokinetic-directed (PKD) dosing was attempted to achieve an area under the concentration time curve of 1000-1500 micromol/min for each dose. Nonrelapse mortality was 28% for PO Bu patients versus 3% for the IV PKD group (P = .01, chi-square test). Actuarial 5-year overall survivals were 28% for patients who received the PO Bu regimen and 58% for patients who received the IV Bu regimen (P = .010, log-rank test), and progression-free survivals were 17% and 50%, respectively (P = .008, log-rank test). After substitution of PKD IV Bu in the BuCyE regimen, we observed lower nonrelapse mortality with increased overall and progression-free survivals in patients with intermediate- and high-risk aggressive non-Hodgkin lymphoma who underwent autoHSCT.

Comparison of graft-versus-host-disease and survival after HLA-identical sibling bone marrow transplantation in ethnic populations.

The association of ethnicity with the incidence of graft-versus-host disease (GVHD) and other clinical outcomes after transplantation is controversial. We compared the results of HLA-identical sibling bone marrow transplantations for leukemia, performed between 1990 and 1999, among different ethnic populations, including 562 Japanese, 829 white Americans, 71 African Americans, 195 Scandinavians, and 95 Irish. Results for adults and children were analyzed separately. Multivariate analyses of adult patients showed that white Americans, African Americans, and Irish cohorts were at significantly higher risk for acute GVHD than Japanese or Scandinavian cohorts (relative risk [RR] = 1.77, P < .001; RR = 1.84, P < .006; RR = 2.22, P < .001, respectively). White Americans, African Americans, and Irish, but not Scandinavians, were at significantly higher risk for early (within 3 months of transplantation) transplant-related mortality (TRM) compared with Japanese (RR = 2.99, P < .001; RR = 5.88, P < .001; RR = 2.66, P < .009, respectively). No differences in the risk for chronic GVHD, relapse, and overall survival were noted. In the pediatric cohort (limited to Japanese and white Americans), white Americans were at significantly higher risk for acute (RR = 1.93; P = .04) and chronic (RR = 3.16; P = .002) GVHD. No differences in other clinical outcomes were noted. Our findings suggest that ethnicity may influence the risk for GVHD, though overall survival rates after transplantation remain similar.

Severity of chronic graft-versus-host disease: association with treatment-related mortality and relapse.

Chronic graft-versus-host disease (cGVHD) is the leading cause of late treatment-related deaths among recipients of allogeneic bone marrow and blood transplants. However, cGVHD is also associated with fewer relapses. We sought to determine whether severity of cGVHD predicts the magnitude of these effects. One impediment to such an analysis is the current limited/extensive grading system for cGVHD because this classification was designed to identify patients likely to benefit from systemic immune suppression and does not capture the severity of multiorgan involvement. We, therefore, first developed a grading system predictive for survival by using data from 1827 HLA-matched sibling allotransplant recipients reported to the International Bone Marrow Transplant Registry (IBMTR). We found Karnofsky performance score, diarrhea, weight loss, and cutaneous and oral involvement to be independent prognostic variables, from which we generated a grading scheme. We tested this scheme, the limited/extensive classification system, and a classification based on clinical impression of overall cGVHD severity (mild/moderate/severe) in parallel analyses of 1092 HLA-matched sibling transplant recipients from the IBMTR and 553 recipients of unrelated donor marrow from the National Marrow Donor Program. Presence of cGVHD was associated with fewer relapses (relative risk [RR], 0.5-0.6) but more treatment-related mortality (RR, 1.8-2.8) in the 3 analyses. No grading scheme correlated cGVHD severity with relapse rates, but all schemes predicted treatment-related mortality. Survival and disease-free survival of the most favorable cGVHD group in each scheme were similar, or better, than those of patients without cGVHD; these patients may not need aggressive or extended immune suppression.