Faculty Bibliography

BACKGROUND:In this trial of the treatment of newly diagnosed multiple myeloma, we compared a protocol that entailed a hematopoietic stem-cell autograft followed by an allograft from an HLA-identical sibling with a protocol of tandem autografts. METHODS:We enrolled 162 consecutive patients with newly diagnosed myeloma who were 65 years of age or younger and who had at least one sibling. All patients were initially treated with vincristine, doxorubicin, and dexamethasone, followed by melphalan and autologous stem-cell rescue. Patients with an HLA-identical sibling then received nonmyeloablative total-body irradiation and stem cells from the sibling. Patients without an HLA-identical sibling received two consecutive myeloablative doses of melphalan, each of which was followed by autologous stem-cell rescue. The primary end points were overall survival and event-free survival. RESULTS:After a median follow-up of 45 months (range, 21 to 90), the median overall survival and event-free survival were longer in the 80 patients with HLA-identical siblings than in the 82 patients without HLA-identical siblings (80 months vs. 54 months, P=0.01; and 35 months vs. 29 months, P=0.02, respectively). Among patients who completed their assigned treatment protocols, treatment-related mortality did not differ significantly between the double-autologous-transplant group (46 patients) and the autograft-allograft group (58 patients, P=0.09), but disease-related mortality was significantly higher in the double-autologous-transplant group (43% vs. 7%, P<0.001). The cumulative incidence rates of grades II, III, and IV graft-versus-host disease (GVHD) combined and of grade IV GVHD in the autograft-allograft group were 43% and 4%, respectively. Overall, 21 of 58 patients (36%) were in complete remission after a median follow-up of 38 months (range, 10 to 72) after allografting. Of the 46 patients who received two autografts, 25 (54%) died. CONCLUSIONS:Among patients with newly diagnosed myeloma, survival in recipients of a hematopoietic stem-cell autograft followed by a stem-cell allograft from an HLA-identical sibling is superior to that in recipients of tandem stem-cell autografts. (ClinicalTrials.gov number, NCT00415987 [ClinicalTrials.gov].).

We assessed the long-term outcome of patients with relapsed acute myeloid (n=86) or acute lymphoid leukemia (n=66), undergoing an allogeneic hemopoietic stem cell transplantation in our unit. The median blast count in the marrow was 30%. Conditioning regimen included total body irradiation (TBI) (10-12 Gy) in 115 patients. The donor was a matched donor (n=132) or a family mismatched donor (n=20). Twenty-two patients (15%) survive disease free, with a median follow-up of 14 years: 18 are off medications. The cumulative incidence of transplant related mortality is 40% and the cumulative incidence of relapse related death (RRD) is 45%. In multivariate analysis of survival, favorable predictors were chronic graft-versus-host disease (GvHD) (P=0.0003), donor other than family mismatched (P=0.02), donor age less than 34 years (P=0.02) and blast count less than 30% (P=0.07). Patients with all four favorable predictors had a 54% survival. In multivariate analysis of relapse, protective variables were the use of TBI (P=0.005) and cGvHD (P=0.01). This study confirms that a fraction of relapsed leukemias is cured with an allogeneic transplant: selection of patients with a blast count <30%, identification of young, human leukocyte antigen-matched donors and the use of total body radiation may significantly improve the outcome.

PURPOSE/OBJECTIVE:Several studies have investigated the feasibility of allogeneic hematopoietic cell transplantations (HCTs) after reduced-intensity conditioning in patients who experienced relapse after myeloablative HCT. Although most studies showed relatively low nonrelapse mortality (NRM) rates and encouraging short-term results, it has yet to be defined which patients would benefit most from these approaches. PATIENTS AND METHODS/METHODS:We analyzed data from 147 patients with hematologic malignancies who experienced treatment failure with conventional autologous (n = 135), allogeneic (n = 10), or syngeneic (n = 2) HCT and were treated with HLA-matched related (n = 62) or unrelated (n = 85) grafts after conditioning with 2 Gy of total-body irradiation with or without fludarabine. RESULTS:Three-year probabilities of NRM, relapse, and overall survival were 32%, 48%, and 27%, respectively, for related recipients, and 28%, 44%, and 44%, respectively, for unrelated recipients. The best outcomes were observed in patients with non-Hodgkin's lymphoma, whereas patients with multiple myeloma and Hodgkin's disease had worse outcomes as a result of high incidences of relapse and progression. Being in partial remission (PR) or complete remission (CR) at HCT (P = .002) and developing chronic graft-versus-host disease (GVHD; P = .03) resulted in lower risks of relapse and progression. Factors associated with better overall survival were PR or CR (P = .01) and lack of comorbidity (P = .03) at HCT and absence of acute GVHD after HCT (P = .06). CONCLUSION/CONCLUSIONS:Encouraging outcomes were seen with allogeneic HCT after nonmyeloablative conditioning in selected patients who had experienced relapse after a high-dose HCT, particularly in patients with non-Hodgkin's lymphoma. Results with unrelated grafts were comparable with results with related grafts.

We retrospectively evaluated the efficacy of bortezomib in 23 patients with multiple myeloma who had relapsed after allografting. Bortezomib was given as single agent to 9 patients (39%) and in combination with steroids in the other 14 (61%). Major toxicities were thrombocytopenia (10/23, 43%) and peripheral neuropathy (12/23, 52%). The overall response rate was 61% (14/23), including 22% (5/23) immunofixation-negative complete remissions. No significant differences in toxicity and response rates were seen between patients treated with bortezomib plus steroids and bortezomib alone. After a median follow-up of 6 months, progression free survival was 6 months. Twenty-one patients are alive, two and five in continuous very good partial and complete remissions, respectively.

BACKGROUND:Bortezomib and thalidomide have shown synergy with melphalan and dexamethasone. We used this 4-drug combination as conditioning before autologous hematopoietic cell infusions. PATIENTS AND METHODS/METHODS:Twenty-six patients with advanced-stage myeloma were treated with melphalan 50 mg/m(2) and bortezomib 1.3 mg/m(2) on days -6 and -3 in association with thalidomide 200 mg and dexamethasone 20 mg on days -6 through -3, followed by hematopoietic cell support on day 0. RESULTS:Nonhematologic toxicities included pneumonia, febrile neutropenia, and peripheral neuropathy. All patients had undergone autologous transplantation at diagnosis, and 13 patients (50%) underwent an additional transplantation at relapse. Responses occurred in 17 of 26 patients (65%), including 1 complete remission, 3 near complete remissions (12%), and 2 very good partial remissions (8%). Response rate was higher than that induced by the previous line of treatment in 12 patients (46%). CONCLUSION/CONCLUSIONS:Melphalan/bortezomib/thalidomide/dexamethasone showed encouraging antimyeloma activity in patients with advanced-stage myeloma.

A new HLA-DRB5 allele, HLA-DRB5*0113, has been identified in an Italian patient during routine HLA typing in order to activate a bone marrow donor search. HLA typing was performed by different molecular biology techniques, and the results showed that the HLA-DRB5*0113 allele differs from HLA-DRB5*010101 allele for three nucleotide substitutions at codons 57 (GAC-->GAT; Asp) and 58 (GCT-->GAG; Ala-->Glu) of exon 2.

OBJECTIVES/OBJECTIVE:Thalidomide combined with conventional chemotherapies including oral melphalan shows significant anti-myeloma activity. To address this issue, feasibility and efficacy of a three drug combination consisting of intravenous (i.v.) melphalan, thalidomide and prednisone [M(i.v.)PT] was evaluated in advanced myeloma patients. PATIENTS AND METHODS/METHODS:Twenty-four advanced myeloma patients were treated with multiple cycles of a regimen consisting of low dose i.v. melphalan (20 mg/m2) at d 1, thalidomide at the dose of 50-100 mg/d given continuously and oral prednisone at the planned dose of 50 mg/d every other day. Intravenous melphalan was administered every fourth month. Median time from diagnosis was 40 months (range: 8-144 months). Fifteen patients (66%) had previously been treated with a combination of thalidomide and dexamethasone or with thalidomide alone. RESULTS:Overall, on an intent-to treat basis, 14 patients responded: three achieved near complete remission (nCR), seven achieved partial response (PR), four minimal response (MR). Six patients showed stable disease (SD) and four-disease progression. Interestingly, of five patients who had previously progressed while on thalidomide and prednisone, one reached nCR, two PR and one MR. After a median follow up of 14 months, median progression free survival was 9 months. Response duration was longer than that induced by the previous line of treatment in eight patients (33%). Thalidomide-associated toxicity mainly consisted of constipation, tingling and sedation. CONCLUSIONS:M(i.v.)PT is an effective regimen, which can overcome resistance to thalidomide plus prednisone in advanced myeloma with acceptable toxicity.