Alberto Mussetti

Reduced-intensity transplantation for lymphomas using haploidentical related donors vs HLA-matched unrelated donors

We evaluated 917 adult lymphoma patients who received haploidentical (n = 185) or HLA-matched unrelated donor (URD) transplantation either with (n = 241) or without antithymocyte globulin (ATG; n = 491) following reduced-intensity conditioning regimens. Haploidentical recipients received posttransplant cyclophosphamide-based graft-versus-host disease (GVHD) prophylaxis, whereas URD recipients received calcineurin inhibitor-based prophylaxis. Median follow-up of survivors was 3 years. The 100-day cumulative incidence of grade III-IV acute GVHD on univariate analysis was 8%, 12%, and 17% in the haploidentical, URD without ATG, and URD with ATG groups, respectively (P = .44). Corresponding 1-year rates of chronic GVHD on univariate analysis were 13%, 51%, and 33%, respectively (P < .001). On multivariate analysis, grade III-IV acute GVHD was higher in URD without ATG (P = .001), as well as URD with ATG (P = .01), relative to haploidentical transplants. Similarly, relative to haploidentical transplants, risk of chronic GVHD was higher in URD without ATG and URD with ATG (P < .0001). Cumulative incidence of relapse/progression at 3 years was 36%, 28%, and 36% in the haploidentical, URD without ATG, and URD with ATG groups, respectively (P = .07). Corresponding 3-year overall survival (OS) was 60%, 62%, and 50% in the 3 groups, respectively, with multivariate analysis showing no survival difference between URD without ATG (P = .21) or URD with ATG (P = .16), relative to haploidentical transplants. Multivariate analysis showed no difference between the 3 groups in terms of nonrelapse mortality (NRM), relapse/progression, and progression-free survival (PFS). These data suggest that reduced-intensity conditioning haploidentical transplantation with posttransplant cyclophosphamide does not compromise early survival outcomes compared with matched URD transplantation, and is associated with significantly reduced risk of chronic GVHD.

Reduced-Intensity Allografting as First Transplantation Approach in Relapsed/Refractory Grades One and Two Follicular Lymphoma Provides Improved Outcomes in Long-Term Survivors.

This study was conducted to compare long-term outcomes in patients with refractory/relapsed grades 1 and 2 follicular lymphoma (FL) after allogeneic (allo) versus autologous (auto) hematopoietic cell transplantation (HCT) in the rituximab era. Adult patients with relapsed/refractory grades 1 and 2 FL undergoing first reduced-intensity allo-HCT or first autograft during 2000 to 2012 were evaluated. A total of 518 rituximab-treated patients were included. Allo-HCT patients were younger and more heavily pretreated, and more patients had advanced stage and chemoresistant disease. The 5-year adjusted probabilities, comparing auto-HCT versus allo-HCT groups for nonrelapse mortality (NRM) were 5% versus 26% (P < .0001); relapse/progression: 54% versus 20% (P < .0001); progression-free survival (PFS): 41% versus 58% (P < .001), and overall survival (OS): 74% versus 66% (P = .05). Auto-HCT was associated with a higher risk of relapse/progression beyond 5 months after HCT (relative risk [RR], 4.4; P < .0001) and worse PFS (RR, 2.9; P < .0001) beyond 11 months after HCT. In the first 24 months after HCT, auto-HCT was associated with improved OS (RR, .41; P < .0001), but beyond 24 months, it was associated with inferior OS (RR, 2.2; P = .006). A landmark analysis of patients alive and progression-free at 2 years after HCT confirmed these observations, showing no difference in further NRM between both groups, but there was significantly higher risk of relapse/progression (RR, 7.3; P < .0001) and inferior PFS (RR, 3.2; P < .0001) and OS (RR, 2.1; P = .04) after auto-HCT. The 10-year cumulative incidences of second hematological malignancies after allo-HCT and auto-HCT were 0% and 7%, respectively. Auto-HCT and reduced-intensity-conditioned allo-HCT as first transplantation approach can provide durable disease control in grades 1 and 2 FL patients. Continued disease relapse risk after auto-HCT translates into improved PFS and OS after allo-HCT in long-term survivors.

Impact of Pretransplantation 18F-fluorodeoxy Glucose-Positron Emission Tomography Status on Outcomes after Allogeneic Hematopoietic Cell Transplantation for Non-Hodgkin Lymphoma

Assessment with (18)F-fluorodeoxy glucose (FDG)-positron emission tomography (PET) before hematopoietic cell transplantation (HCT) for lymphoma may be prognostic for outcomes. Patients with chemotherapy-sensitive non-Hodgkin lymphoma (NHL) undergoing allogeneic HCT reported to the Center of International Blood and Marrow Transplantation Registry between 2007 and 2012 were included. Pre-HCT PET status (positive versus negative) was determined by the reporting transplantation centers. We analyzed 336 patients; median age was 55 years and 60% were males. Follicular lymphoma (n = 104) was more common than large cell (n = 85), mantle cell (n = 69), and mature natural killer or T cell lymphoma (n = 78); two thirds of the cohort received reduced-intensity conditioning; one half had unrelated donor grafts. Patients underwent PET scanning a median of 1 month (range, .07 to 2.83 months) before HCT; 159 were PET positive and 177 were PET negative. At 3 years, relapse/progression, progression-free survival (PFS), and overall survival (OS) in PET-positive versus PET-negative groups were 40% versus 26%; P = .007; 43% versus 47%; P = .47; and 58% versus 60%; P = .73, respectively. On multivariate analysis, a positive pretransplantation PET was associated with an increased risk of relapse/progression (risk ratio [RR], 1.86; P = .001) but was not associated with increased mortality (RR, 1.29, 95% confidence interval [CI], .96 to 1.7; P = .08), therapy failure (RR, 1.32; 95% CI, .95 to 1.84; P = .10), or nonrelapse mortality (RR, .75; 95% CI, .48 to 1.18; P = .22). PET status conferred no influence on graft-versus-host disease. A positive PET scan before HCT is associated with increased relapse risk but should not be interpreted as a barrier to a successful allograft. PET status does not appear to predict survival after allogeneic HCT for NHL.

Long-term survival outcomes of reduced-intensity allogeneic or autologous transplantation in relapsed grade 3 follicular lymphoma

Grade 3 follicular lymphoma (FL) has aggressive clinical behavior. To evaluate the optimal first transplantation approach in relapsed/refractory grade 3 FL patients, we compared the long-term outcomes after allogeneic (allo-) vs autologous hematopoietic cell transplantation (auto-HCT) in the rituximab era. A total of 197 patients undergoing first reduced-intensity conditioning (RIC) allo-HCT or first auto-HCT during 2000–2012 were included. Rituximab-naive patients were excluded. Allo-HCT recipients were younger, more heavily pretreated and had a longer interval between diagnosis and HCT. The 5-year probabilities of non-relapse mortality (NRM), relapse/progression, PFS and overall survival (OS) for auto-HCT vs allo-HCT groups were 4% vs 27% (P<0.001), 61% vs 20% (P<0.001), 36% vs 51% (P=0.07) and 59% vs 54% (P=0.7), respectively. On multivariate analysis, auto-HCT was associated with reduced risk of NRM (relative risk (RR)=0.20; P=0.001). Within the first 11 months post HCT, auto- and allo-HCT had similar risks of relapse/progression and PFS. Beyond 11 months, auto-HCT was associated with higher risk of relapse/progression (RR=21.3; P=0.003) and inferior PFS (RR=3.2; P=0.005). In the first 24 months post HCT, auto-HCT was associated with improved OS (RR=0.42; P=0.005), but in long-time survivors (beyond 24 months) it was associated with inferior OS (RR=3.6; P=0.04). RIC allo-HCT as the first transplant approach can provide improved PFS and OS, in long-term survivors.

Autoimmune diseases during treatment with immunomodulatory drugs in multiple myeloma: selective occurrence after lenalidomide

Abstract Immunomodulatory drugs (IMiDs) may favor autoimmune disease (AD) occurrence. We conducted a retrospective study to evaluate AD occurrence among IMiD-treated patients with myeloma. Patients were grouped into three classes depending on the type of IMiD engaged. The first group included patients treated with thalidomide (Thal) (n = 474), the second group with lenalidomide (Len) (n = 140) and patients in the third group were first treated with Thal followed by Len (Thal-Len) (n = 94). Absolute risk of AD was 0.4% for patients treated with Thal, 4.3% for Len and 1.1% for Thal-Len. ADs manifested prevalently as autoimmune cytopenias (55%), although we observed one vasculitis, one optic neuritis, one Graves’ disease and one polymyositis. ADs occurred preferentially in the first months of IMiD treatment. A previous autologous transplant was shown to be a significant risk factor. All ADs were managed with IMiD discontinuation and steroids, resolving in a few weeks, except for Graves’ disease and polymyositis.

EXTRACORPOREAL PHOTOPHERESIS (ECP) FOR TREATEMENT OF ACUTE AND CHRONIC GRAFT VERSUS HOST DISEASE: AN ITALIAN MULTICENTRIC RETROSPECTIVE ANALYSIS ON 94 PATIENTS ON BEHALF OF THE GRUPPO ITALIANO TRAPIANTO DI MIDOLLO OSSEO (GITMO)

Background Extracorporeal photopheresis (ECP) is considered a valid second-line treatment for acute and chronic graft versus host disease (GVHD). Methods Ninety-four patients with acute GVHD (aGVHD) (n = 45) and chronic GVHD (cGVHD) (n = 49), retrospectively recruited in 6 Italian centers, were submitted to ECP for second-line treatment. At the time of ECP, 22 (49%) and 23 (51%) of 45 patients with aGHVD were nonresponsive and in partial remission (PR) after steroids, respectively, and all the 49 patients with cGVHD were steroid refractory. Results Forty-one (91%) of 45 patients with aGVHD achieved complete remission (CR) after ECP. Fifteen (33%) of 45 patients developed cGVHD. The CR rate in patients who started ECP being nonresponsive and in PR after steroid was 86% and 96%, respectively. After a median follow-up of 20 months (range, 2-72), 15 (33%) of 45 patients developed cGHVD and 16 (35%) of 45 patients died, in 3 cases for aGVHD. A trend for a better survival was seen among patients who started ECP in PR after steroid (80% vs 50% at 2 years; P = 0.07). Overall, 22 (45%) of 49 patients and 17 (35%) of 49 patients with steroid refractory cGHVD achieved CR and PR after ECP, respectively. After a median follow-up of 27 months, 44 (90%) of 49 patients are alive, 21 of whom (48%) are on steroid. Conclusions Extracorporeal photopheresis is confirmed as an effective second-line treatment in both aGVHD and cGVHD, because it can induce a response in more than 80% of the patients and a long-term survival in at least 50% of the cases.

Non-myeloablative allogeneic hematopoietic stem cell transplantation for adults with relapsed and refractory mantle cell lymphoma: a single-center analysis in the rituximab era

Relapsed and refractory (rel/ref) mantle cell lymphoma (MCL) portend a dismal prognosis. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) represents the only potentially curative therapy in this setting. We analyzed the survival outcomes of 29 recipients of non-myeloablative allo-HSCT for rel/ref MCL, and studied possible prognostic factors in this setting. The cumulative incidences of disease progression and non-relapse mortality at 3 years were 28% (95% confidence interval (CI): 13–46%) and 29% (95% CI: 13–47%), respectively. The cumulative incidence of grade II–IV acute GvHD at days +100 and +180 was 34% (95% CI: 18–52%) and 45% (95% CI: 26–62%), respectively. With a median follow-up in survivors of 53 (range 24–83) months, the 3-year overall survival (OS) and PFS were 54% (95% CI: 38–76%) and 41% (95% CI: 26–64%), respectively. In vivo T-cell depletion with alemtuzumab (n=6) was associated with inferior 3-year PFS (0% vs 51%, P=0.007) and OS (17% vs 64%, P=0.014). Conversely, a second-line international prognostic index (sIPI) at transplantation equal to 0 (no risk factors) was associated with an improved 3-year PFS (52% vs 22%, P=0.020) and OS (71% vs 22%, P=0.006) compared with sIPI ⩾1. Performing an allo-HSCT before 2007 was associated with a decreased 3-year OS (25% vs 76%, P=0.015) but not with a significantly inferior PFS (17% vs 59%, P=0.058). In this single-center series, we report encouraging results with allo-HSCT for patients with rel/ref MCL. High alemtuzumab doses should probably be avoided in this context.

Haploidentical Allogeneic Hematopoietic Cell Transplantation for Multiple Myeloma Using Post-Transplantation Cyclophosphamide Graft-versus-Host Disease Prophylaxis

Allogeneic (allo) hematopoietic cell transplantation (HCT) currently represents the only potentially curative therapy for patients affected by multiple myeloma (MM). Up to 30% of patients in western countries do not have a matched donor. Haploidentical HCT (haplo-HCT) may be an option, but currently, there are little available data regarding this treatment. We analyzed survival outcomes of 30 heavily pretreated MM patients who received haplo-HCT with post-transplantation cyclophosphamide as graft-versus-host-disease (GVHD) prophylaxis. Median neutrophil and platelet engraftments at day +30 were 87% (95% confidence interval [CI], 66% to 95%) and 60% (95% CI, 40% to 75%), respectively. The cumulative incidences of relapse or progression of disease (PD) and nonrelapse mortality at 18 months were 42% (95% CI, 23% to 59%) and 10% (95% CI, 2% to 24%), respectively. The cumulative incidence of grade II to IV acute GVHD at day +100 was 29% (95% CI, 14% to 47%). The cumulative incidence of chronic GVHD at 18 months was 7% (95% CI, 1% to 21%). With a median follow-up in survivors of 25 months (range, 15 to 73 months), the 18-month progression-free survival (PFS) and overall survival (OS) were 33% (95% CI, 17% to 50%) and 63% (95% CI, 44% to 78%), respectively. No differences were observed between peripheral blood and bone marrow graft in terms of engraftment, GVHD, or PD incidence. Chemorefractory disease at transplantation was associated with a lower/reduced 18-month PFS (9% versus 47%, P = .01) and OS (45% versus 74%, P = .03). This was explained by a higher PD incidence (55% versus 33%, P = .05). In this multicenter study, we report encouraging results with haplo-HCT for patients with heavily pretreated MM.

Bendamustine in relapsed/refractory multiple myeloma: The "real-life" side of the moon

Bendamustine is an old bi-functional alkylating agent which, thanks to its extended efficacy and good tolerability, is living a second youth with growing use in several lympho-proliferative maligna...

Post-transplant cyclophosphamide, a promising anti-graft versus host disease prophylaxis: where do we stand?

ABSTRACT Introduction: Post transplant cyclophosphamide (PT/Cy) in association to other immunosuppressive agents or alone has emerged as a promising pharmacological strategy in the setting of allogeneic hematopoietic cell transplant (allo-HCT). Its safety profile and effectiveness in reducing GvHD (acute GvHD incidence comprised between 15 and 30%, chronic GvHD 20–30% in the haploidentical setting) contributed to the spreading of this technique all over the world. Areas covered: This review summarizes the use of PT/Cy in the setting of allo-HCT, both for oncological and non-malignant hematological diseases. Recent studies showed the feasibility of more intense conditioning regimens instead of the original NMAC. The use of peripheral blood stem cells instead of bone marrow as graft source (slightly increase of acute GvHD grade 2 but no differences in survival outcomes) was another significant variation to the original protocol. Later on, PT/Cy alone or in combination with other immunosuppressive agents (ATG, sirolimus, cyclosporine) were tested in the HLA-matched donor setting where lower GvHD rates are reported (acute GvHD grade 3 of 5–10% and chronic GvHD of 10–20%) Expert commentary: The best graft source and type of donor is still ongoing. Moreover, the research of the best pharmacological partner of PT/Cy remains an open question.