Faculty Bibliography

Multiple myeloma relapsing after allogeneic stem cell transplantation (alloSCT) has a poor outcome. To assess the safety and efficacy of bortezomib and dexamethasone (VD) combination followed by donor lymphocyte infusions (DLIs) in myeloma patients relapsing or progressing after alloSCT, a prospective phase II study was designed. The treatment plan consisted of three VD courses followed by escalated doses of DLIs in case of response or at least stable disease. Nineteen patients were enrolled with a median age of 57 years (range, 33 to 67); 14 patients were allografted from human leukocyte antigen-identical siblings and 5 from alternative donors. Sixteen of 19 patients received the planned treatment, but 3 patients did not: 2 patients because of disease progression and 1 refused. After the VD phase the response rate was 62%, with 1 complete remission, 6 very good partial remissions, 5 partial remissions, 2 patients with stable disease, and 5 with progressive disease. After the DLI phase, the response rate was 68%, but a significant upgrade of response was observed: 3 stringent complete remissions, 2 complete remissions, 5 very good partial remissions, 1 partial remission, 4 with stable disease, and 1 with progressive disease. With a median follow-up of 40 months (range, 29 to 68), the 3-year progression-free survival and overall survival rates were 31% and 73%, respectively. Neither unexpected organ toxicities, in particular severe neuropathy, nor severe acute graft-versus-host disease flares were observed. VD-DLIs is a safe treatment for multiple myeloma patients relapsing or progressing after alloSCT and may be effective.

The median survival of women with metastatic breast cancer (MBC) is 18-24 months, and fewer than 5% are alive and disease free at 5 years. We report toxicity and survival in a cohort of MBC patients receiving high-dose chemotherapy (HDC) with autologous hematopoietic SCT (AHSCT) in Italy between 1990 and 2005. Data set for survival analysis has been obtained for 415 patients. Clinical parameters including probability of transplant-related mortality (TRM), PFS and OS. With a median follow-up of 27 months (range 0-172), OS and PFS at 5 and 10 years in the whole population were 47/23 and 32/14%, respectively. A total 239 patients are alive with a median follow-up of 33 months (range 2-174). Survival was significantly more pronounced in patients harboring hormone receptor positive tumors (P=0.028), without visceral metastases (P=0.009) and in women with chemosensitive disease (P<0.0001). Sixty eight patients (20.4%) who received HDC in partial response, stable or progressive disease underwent conversion to CR. TRM was 2.5% overall and 1.3% since 2000. Our findings suggest that could be a role for HDC and AHSCT in delaying disease progression and possibly cure a subset of MBC patient harboring chemosensitive tumors.

INTRODUCTION/BACKGROUND:There are considerable concerns regarding the appropriate use of health care resources to reduce costs and waiting lists associated with autologous hematopoietic progenitor cell transplantation (AHPCT). One of the strategies to reach this goal is outpatient-based (OpB) AHPCT. AREAS COVERED/METHODS:We reviewed all the reported experiences in this field and illustrated the various models of OpB AHPCT. EXPERT OPINION/CONCLUSIONS:The role of high-dose melphalan (HDM) followed by AHPCT in the treatment of Multiple Myeloma (MM) continues to evolve in the novel agent era and the International Myeloma Working Group recommends that AHPCT should be offered at some point in the course of the treatment program for a medically fit patient. The relatively short neutropenia and the limited extra-marrow toxicity after HDM support the hypothesis that MM patients are the most suitable for outpatient transplant programs. Various models have shown that the procedure is feasible and safe and may highly contribute to shorten waiting lists and to considerably cut health costs, with an improvement of quality of life. Ideal candidates may be those who are asymptomatic and fully active, who have a full-time caregiver and who can reside within easy reach from the transplant center.

A non myeloablative conditioning with total lymphoid irradiation (TLI) and antithymocyte globulin (ATG) was shown to protect against graft-versus-host disease (GVHD). To evaluate the effects of TLI-ATG in a multicenter study, 45 heavily pretreated patients, median age 51, with lymphoid (n = 38) and myeloid (n = 7) malignancies were enrolled at 9 centers. Twenty-eight patients (62%) received at least 3 lines of treatment before allografting, and 13 (29%) had refractory/relapsed disease at the time of transplantation. Peripheral blood hematopoietic cells were from HLA identical sibling (n = 30), HLA-matched (n = 9), or 1 antigen HLA-mismatched (n = 6) unrelated donors. A cumulative TLI dose of 8 Gy was administered from day -11 through -1 with ATG at the dose of 1.5 mg/kg/day (from day -11 through -7). GVHD prophylaxis consisted of cyclosporine and mycophenolate mofetil. Donor engraftment was reached in 95% of patients. Grade II to IV acute GVHD (aGVHD) developed in 6 patients (13.3%), and in 2 of these patients, it developed beyond day 100. Incidence of chronic GVHD (cGVHD) was 35.8%. One-year nonrelapse mortality was 9.1%. After a median follow-up of 28 months (range, 3-57 months) from transplantation, median overall survival was not reached, whereas median event-free survival was 20 months. This multicenter experience confirms that TLI-ATG protects against GVHD and maintains graft-vs-tumor effects.

An unrelated donor (UD) search was submitted to the Italian Bone Marrow Donor Registry between February 2002 and December 2004, for 326 consecutive patients with hematological malignancies, eligible for a reduced intensity conditioning (RIC) UD transplant. Only two regimens were allowed: melphalan, alemtuzumab, fludarabine and total body irradiation of 200 cGy (regimen A) and thiotepa, cyclophosphamide, anti-thymocyte globulin (regimen B). The outcome of patients receiving an UD transplant (n=121) was compared with patients who did not find a donor (n=205), in a time dependent analysis, correcting for time to transplant. The median follow up from activation of donor search was 6.1 years. UD transplant was associated with a significantly better survival in patients with acute leukemia and non-Hodgkin's lymphoma (NHL) whereas only a favorable trend was documented for Hodgkin's disease. No survival benefit was registered for chronic leukemias. The outcome of the two different conditioning regimens was comparable, in terms of survival, transplant-related mortality and graft versus host disease. In conclusion, finding an UD and undergoing a RIC transplant significantly improves survival of patients with acute leukemia and NHL. The advantage is less clear for HD and chronic leukemias. The role of different conditioning regimens remains to be elucidated by prospective clinical trials.

Allogeneic stem cell transplantation (allo-SCT) using reduced-intensity conditioning (RIC) is a feasible procedure in selected patients with relapsed multiple myeloma (MM), but its efficacy remains a matter of debate. The mortality and morbidity related to the procedure and the rather high relapse risk make the use of allo-SCT controversial. In addition, the availability of novel antimyeloma treatments, such as bortezomib and immunomodulatory agents, have made allo-SCT less appealing to clinicians. We investigated the role of RIC allo-SCT in patients with MM who relapsed after autologous stem cell transplantation and were then treated with a salvage therapy based on novel agents. This study was structured similarly to an intention-to-treat analysis and included only those patients who underwent HLA typing immediately after the relapse. Patients with a donor (donor group) and those without a suitable donor (no-donor group) were compared. A total of 169 consecutive patients were evaluated retrospectively in a multicenter study. Of these, 75 patients found a donor and 68 (91%) underwent RIC allo-SCT, including 24 from an HLA-identical sibling (35%) and 44 from an unrelated donor (65%). Seven patients with a donor did not undergo allo-SCT for progressive disease or concomitant severe comorbidities. The 2-year cumulative incidence of nonrelapse mortality was 22% in the donor group and 1% in the no-donor group (P < .0001). The 2-year progression-free survival (PFS) was 42% in the donor group and 18% in the no-donor group (P < .0001). The 2-year overall survival (OS) was 54% in the donor group and 53% in the no-donor group (P = .329). In multivariate analysis, lack of a donor was a significant unfavorable factor for PFS, but not for OS. Lack of chemosensitivity after salvage treatment and high-risk karyotype at diagnosis significantly shortened OS. In patients who underwent allo-SCT, the development of chronic graft-versus-host disease had a significant protective effect on OS. This study provides evidence for a significant PFS benefit of salvage treatment with novel drugs followed by RIC allo-SCT in patients with relapsed MM who have a suitable donor.

Rescue chemotherapy or autologous stem cell transplantation (autoSCT) gives disappointing results in relapsed peripheral T-cell lymphomas (PTCLs). We have retrospectively evaluated the long-term outcome of 52 patients receiving allogeneic SCT for relapsed disease. Histologies were PTCL-not-otherwise specified (n=23), anaplastic large-cell lymphoma (n=11), angioimmunoblastic T-cell lymphomas (n=9) and rare subtypes (n=9). Patients were allografted from related siblings (n=33, 64%) or alternative donors (n=13 (25%) from unrelated and 6 (11%) from haploidentical family donors), following reduced-intensity conditioning (RIC) regimens including thiotepa, fludarabine and cyclophosphamide. Most of the patients had chemosensitive disease (n=39, 75%) and 27 (52%) failed a previous autoSCT. At a median follow-up of 67 months, 27 of 52 patients were found to be alive (52%) and 25 (48%) were dead (n=19 disease progression, n=6 non-relapse mortality (NRM)). The cumulative incidence (CI) of NRM was 12% at 5 years. Extensive chronic graft-versus-host disease increased the risk of NRM (33% versus 8%, P=0.04). The CI of relapse was 49% at 5 years, influenced by disease status at the time of allografting (P=0.0009) and treatment lines (P=0.007). Five-year overall survival and progression-free survival (PFS) were 50% (95% CI, 36 - 63%) and 40% (95% CI, 27 - 53%), respectively. The current PFS was 44% (95% CI, 30-57%). In all, 8 out of 12 patients (66%) who received donor-lymphocytes infusions for disease progression had a response. At multivariable analysis, refractory disease and age over 45 years were independent adverse prognostic factors. RIC allogeneic SCT is an effective salvage treatment with a better outcome for younger patients with chemosensitive disease.

We retrospectively analyzed 55 patients given a fixed dose of rituximab (200 mg) on day+5 after an alternative donor transplant, to prevent EBV DNA-emia; 68 alternative transplants who did not receive prophylactic rituximab served as controls. The two groups were comparable for donor type, and all patients received anti-thymocyte globulin in the conditioning regimen. Rituximab patients had a significantly lower rate of EBV DNA-emia 56 vs 85% (P=0.0004), a lower number of maximum median EBV copies (91 vs 1321/10(5) cells, P=0.003) and a significantly lower risk of exceeding 1000 EBV copies per 10(5)cells (14 vs 49%, P=0.0001). Leukocyte and lymphocyte counts were lower on day +50 and+100 in rituximab patients, whereas Ig levels were comparable. The cumulative incidence of grade II-IV acute GvHD was significantly reduced in rituximab patients (20 vs 38%, P=0.02). Chronic GvHD was comparable. There was a trend for a survival advantage for patients receiving rituximab (46 vs 40%, P=0.1), mainly because of lower transplant mortality (25 vs 37%, P=0.1). Despite the drawback of a retrospective study, these data suggest that a fixed dose of rituximab on day +5 reduces the risk of a high EBV load, and also reduces acute GvHD.

Extramedullary recurrence in multiple myeloma patients has been reported after both autologous and allogeneic hematopoietic cell transplantation and, more recently, after treatment with so-called new drugs with potent antimyeloma activity. Only a very few sizable reports focused on its clinical presentation and its incidence, which may be highly underestimated, and most observations are based on single patients reported from several institutions. Given the unusual sites of recurrence, diagnosis may be rather difficult and delayed treatment may play a relevant role in prognosis. Here we report a case of a myeloma patient, initially treated with an allograft, who enjoyed an eleven-year disease-free remission with very good quality of life. She eventually relapsed first with an extramedullary plasmacytoma in the breast and, two years later, with a right atrial cardiac mass.

CONTEXT/BACKGROUND:A minimally toxic nonmyeloablative regimen was developed for allogeneic hematopoietic cell transplantation (HCT) to treat patients with advanced hematologic malignancies who are older or have comorbid conditions. OBJECTIVE:To describe outcomes of patients 60 years or older after receiving minimally toxic nonmyeloablative allogeneic HCT. DESIGN, SETTING, AND PARTICIPANTS/METHODS:From 1998 to 2008, 372 patients aged 60 to 75 years were enrolled in prospective clinical HCT trials at 18 collaborating institutions using conditioning with low-dose total body irradiation alone or combined with fludarabine, 90 mg/m(2), before related (n = 184) or unrelated (n = 188) donor transplants. Postgrafting immunosuppression included mycophenolate mofetil and a calcineurin inhibitor. MAIN OUTCOME MEASURES/METHODS:Overall and progression-free survival were estimated by Kaplan-Meier method. Cumulative incidence estimates were calculated for acute and chronic graft-vs-host disease, toxicities, achievement of full donor chimerism, complete remission, relapse, and nonrelapse mortality. Hazard ratios (HRs) were estimated from Cox regression models. RESULTS:Overall, 5-year cumulative incidences of nonrelapse mortality and relapse were 27% (95% CI, 22%-32%) and 41% (95% CI, 36%-46%), respectively, leading to 5-year overall and progression-free survival of 35% (95% CI, 30%-40%) and 32% (95% CI, 27%-37%), respectively. These outcomes were not statistically significantly different when stratified by age groups. Furthermore, increasing age was not associated with increases in acute or chronic graft-vs-host disease or organ toxicities. In multivariate models, HCT-specific comorbidity index scores of 1 to 2 (HR, 1.58 [95% CI, 1.08-2.31]) and 3 or greater (HR, 1.97 [95% CI, 1.38-2.80]) were associated with worse survival compared with an HCT-specific comorbidity index score of 0 (P = .003 overall). Similarly, standard relapse risk (HR, 1.67 [95% CI, 1.10-2.54]) and high relapse risk (HR, 2.22 [95% CI, 1.43-3.43]) were associated with worse survival compared with low relapse risk (P < .001 overall). CONCLUSION/CONCLUSIONS:Among patients aged 60 to 75 years treated with nonmyeloablative allogeneic HCT, 5-year overall and progression-free survivals were 35% and 32%, respectively.