T-cell-depleted reduced-intensity transplantation followed by donor leukocyte infusions to promote graft-versus-lymphoma activity results in excellent long-term survival in patients with multiply relapsed follicular lymphoma.

PURPOSE: Follicular lymphoma (FL) is an indolent disorder that is treatable but considered incurable with chemotherapy alone. The curative potential of allogeneic transplantation using conventional myeloablative conditioning has been demonstrated, but this approach is precluded in the majority of patients with FL because of excessive toxicity. Thus, reduced-intensity conditioning regimens are being explored. PATIENTS AND METHODS: This study reports the outcome of 82 consecutive patients with FL who underwent transplantation using fludarabine, melphalan, and alemtuzumab for in vivo T-cell depletion. Patients were heavily pretreated, having received a median of four lines of prior therapy, and 26% had experienced treatment failure with previous autologous transplantation. Median patient age was 45 years, and 52% of patients received stem cells from unrelated donors. RESULTS: With a median follow-up time of 43 months, the nonrelapse mortality was 15% at 4 years (8% for sibling and 22% for unrelated donor transplantations), acute grade 2 or 3 graft-versus-host disease (GVHD) occurred in 13%, and the incidence of extensive chronic GVHD was only 18%. Although relapse risk was 26%, this was significantly reduced where mixed chimerism had been converted to full donor chimerism by the use of donor lymphocyte infusion (DLI; P = .03). In addition, 10 (77%) of 13 patients given DLI for relapse after transplantation experienced remission, with nine of these responses being sustained. Current progression-free survival at 4 years was 76% for the whole cohort (90% for those with sibling donors and 64% for those with unrelated donors). CONCLUSION: The excellent long-term survival with associated low rates of GVHD and the frequency and durability of DLI responses make this an extremely encouraging strategy for the treatment and potential cure of FL.

Evidence for direct involvement of epirubicin in the formation of chromosomal translocations in t(15;17) therapy-related acute promyelocytic leukemia.

Therapy-related acute promyelocytic leukemia (t-APL) with t(15;17)(q22;q21) involving the PML and RARA genes is associated with exposure to agents targeting topoisomerase II (topoII), particularly mitoxantrone and epirubicin. We previously have shown that mitoxantrone preferentially induces topoII-mediated DNA damage in a "hotspot region" within PML intron 6. To investigate mechanisms underlying epirubicin-associated t-APL, t(15;17) genomic breakpoints were characterized in 6 cases with prior breast cancer. Significant breakpoint clustering was observed in PML and RARA loci (P = .009 and P = .017, respectively), with PML breakpoints lying outside the mitoxantrone-associated hotspot region. Recurrent breakpoints identified in the PML and RARA loci in epirubicin-related t-APL were shown to be preferential sites of topoII-induced DNA damage, enhanced by epirubicin. Although site preferences for DNA damage differed between mitoxantrone and epirubicin, the observation that particular regions of the PML and RARA loci are susceptible to these agents may underlie their respective propensities to induce t-APL.

Complete molecular responses are achieved after reduced intensity stem cell transplantation and donor lymphocyte infusion in chronic myeloid leukemia.

Patients with newly diagnosed chronic phase chronic myeloid leukemia were treated with imatinib mesylate (IM) for 6 to 12 months to establish disease control, before reduced intensity stem cell transplantation (RISCT). Escalating doses of donor lymphocyte infusions were given from 6 months after transplantation to eradicate residual disease. A total of 18 patients entered the study and 15 received RISCT (median follow-up, 31 months). RISCT was well tolerated with rapid engraftment, short inpatient stays, and few readmissions. Viral reactivation was common, although extensive graft-versus-host disease occurred infrequently. Donor lymphocyte infusions were given as part of the RISCT protocol in 13 of 15 patients. BCR-ABL transcripts continued to decrease after RISCT, and 8 (53%) patients achieved sustained undetectable levels. All patients are currently off IM. Although IM is now established as first-line therapy for chronic phase chronic myeloid leukemia, this protocol is a safe, well-tolerated, and effective strategy in these patients. This study is registered at http://www.controlled-trials.com as ISRCTN86187144.

Response to thalidomide in chemotherapy-resistant mantle cell lymphoma: a case report.

Mantle cell lymphoma is an aggressive B-cell lymphoma with a poor median survival despite conventional therapy. Here, we present the case of a patient with multiply relapsed mantle cell lymphoma, having failed treatment with chemotherapy, steroids and rituximab. He was treated with single-agent thalidomide at a dose of 800 mg daily and entered a good partial remission which was maintained for the next 6 months. There is clearly a need for further studies of thalidomide in mantle cell lymphoma to confirm this promising initial result.

Dose escalation therapy in previously untreated patients with multiple myeloma following Z-Dex induction treatment.

A phase I-II study of high-dose (HD) alkylating agents in newly diagnosed patients with multiple myeloma after maximum response to Z-Dex (idarubicin, dexamethasone) therapy and DHAP (cisplatin, HD cytosine arabinoside, dexamethasone), stem cell mobilization is reported. Twenty-six patients, median age 56 years (range 42-66), completed Z-Dex chemotherapy and peripheral blood stem cells (PBSC) were mobilized with DHAP. Patients then preceded to cyclophosphamide (HD Cy: 6 g/m(2)) with granulocyte colony-stimulating factor followed by busulphan-melphalan-conditioned PBSC autograft. Interferon alpha was introduced at 3 months post transplant as maintenance therapy. Six patients failed to complete the full protocol. Median time from diagnosis to transplantation was 8 months (range 6-12). Mean CD34+ cell dose collected was 15.8 x 10(6)/kg (CI 11.8, 19.8). Median time from DHAP to HD-Cy was 6 weeks (range 4-12) and from HD-Cy to transplant was 8 weeks (range 6-12). The median follow-up was 36 months (range 6-63). On an intent-to-treat basis, the response rates were three complete response (CR, 12%), 21 partial response (PR, 80%) and two stable disease (SD, 8%) post Z-Dex, five CR (19%) and 21 PR (81%) post HD-Cy, and 14 CR (54%) and 12 PR (46%) post transplant. The treatment-related mortality (TRM) was 4% (1 patient). Median overall survival (OS) and progression-free survival (PFS) have not been reached; estimated values were 60 and 48 months respectively. The 3-year OS and PFS were 72% and 62%. Actuarial 5-year OS and event-free survival were 49% and 32%. DHAP produces effective PBSC mobilization and sequential HD therapy, including autologous PBSCT, in patients who received Z-Dex; this offers significant durable disease response rates with acceptable TRM.