ALBERT

Description: Allogeneic approaches employing low dose TBI nonmyeloablative conditionings reported a dramatic reduction of transplant-related mortality (TRM) compared to conventional high dose regimens in newly diagnosed multiple myeloma (MM) (Maloney et al, Blood, 2003). The role of allografting, however, compared to autologous HCT remains to be determined. From September 1999 to July 2004, 241 consecutive MM patients, up to the age of 65, were diagnosed at five academic Italian Institutions. Overall, 194/241 had natural siblings (Table 1): 158/194 (81%) were HLA typed, while 36/194 (19%) were not typed for the following reasons: patients not eligible for high dose chemotherapy (n. 14); siblings not eligible for peripheral hematopoietic cell (PHC) donation (n.11); patient refusal to high dose chemotherapy (n. 9), unknown (n.2). Seventy-six/158 (48%) with a matched donor were offered a tandem autologous- nonmyeloablative allogeneic HCT approach. Eventually, 56/76 (73%), the “auto-allo group”, were enrolled while 20 did not enter the tandem program as 5 siblings (5/76, 7%) were not eligible for PHC donation, 5 patients refused an allogeneic HCT, and 10 patients preferred allografting as a possible salvage treatment. Of 102 patients without matched donors or after refusal to allografting, 73, “double-auto group”, underwent a standard double autologous transplant while 29 received less intense treatments because of clinical conditions or patient preference. Table 1 Newly diagnosed pts 241 With sibs/without sibs 194 /47 (total 241) HLA typed /not HLA typed 158 /36 (total 194) Matched sibs /No matched sibs 76 /82 (total 158) Auto-Allo”/“Double Auto”/Other”“ 56 /73 /29 (total 158) After induction chemotherapy, patients of both groups underwent G-CSF mobilised autografting with high dose melphalan (200 mg/m2). In the “auto-allo” group, the autologous HCT was followed, 2-4 months later, by low dose (2.0 Gy) TBI, allogeneic PHC infusion, and post transplant mycophenolate mofetil and cyclosporin. In the “double-auto group”, patients received a second autologous HCT. Patients characteristics were as follows: age: 54 (range 34–65) vs 53 (range 33–64) (p=ns); stage III myeloma: 77% vs 64% (p=0.03); beta 2 microglobulin 〉 2,5 mg/dl: 75% vs 59% (p=0.005), for the “auto-allo group” and for “the double-auto group”, respectively. At the time of this analysis, 56/56 of the “auto-allo group” and 55/73 of “the double-auto group” had completed the transplant programs. After median follow up of 3 years (range 11–80 months), TRM was 11% vs 4% (p=0.09); complete remission rates, defined as the disappearance of the monoclonal paraprotein by immunofixation, were 46% vs 16% (p=0.0001); overall survivals were 84% versus 62% (p=0.003); progression free survivals were 75% vs 41% (p=0.00008); event free survivals were 61% (34/56)% vs 38% (30/73) (p=0.006) in the “auto-allo group” and in the “double-auto” group, respectively. Longer follow up is needed, however data suggest that the “auto- non myeloablative allo” approach is not inferior to “double autologous” HCT in newly diagnosed MM.

Description: The development of nonmyeloablative conditionings has recently reduced the transplant-related mortality (TRM) and extended the eligible age for transplantation up to 65–70 years. From January 2000 to June 2005, 106 newly diagnosed patients younger than 65 years were enrolled in a prospective phase II study at 15 Italian Centers. Fifty-eight were also previously described in a comparison of autografting with allografting based on a genetic randomisation (Bruno et al. N Engl J Med 2007). Here we report on a larger GITMO experience with a longer follow-up. Induction chemotherapy consisted of VAD-based regimens, followed by a cytoreductive autograft with melphalan 200 mg/m2, and by a non-myeloablative 2 Gy TBI-based allograft from an HLA-identical sibling. Graft-vs-host disease (GVHD) prophylaxis included cyclosporin and mycophenolate mofetil. Primary endpoints were overall (OS) and event-free (EFS) survivals. Secondary endpoint was TRM. One-hundred-two (96%) patients, median age 54 (30–65), completed the tandem program whereas 4 withdrew their consent. After a median follow-up of 54 (21–94) months, OS was not reached and median EFS was 35 (31–56) months post-transplant. Incidences of acute grade II-IV GHVD and extensive chronic GVHD were 40% and 50% respectively. Fourteen (13%) patients died from TRM, 14 (13%) from disease progression, 2 from lung cancer (2%) and 1 from lymphoma (1%). Overall response, defined as complete (CR) and partial remission, was 91% (93/102), with 53 patients achieving CR. Overall 39/102 patients relapsed, however only 8/53 of those who reached CR post-transplant. By multivariate-analysis disease response prior to allografting was significantly associated with longer OS (HR 0.27, CI 0.09–0.80, p

Description: CD34+ hematopoietic stem cells from normal individuals and from patients with chronic myelogenous leukemia can be induced to differentiate into dendritic cells (DC). The aim of the current study was to determine whether acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) cells could be induced to differentiate into DC. CD34+ AML-M2 cells with chromosome 7 monosomy were cultured in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor  (TNF), and interleukin-4 (IL-4). After 3 weeks of culture, 35% of the AML-M2 cells showed DC morphology and phenotype. The DC phenotype was defined as upmodulation of the costimulatory molecules CD80 and CD86 and the expression of CD1a or CD83. The leukemic nature of the DC was validated by detection of chromosome 7 monosomy in sorted DC populations by fluorescence in situ hybridization (FISH). CD34+ leukemic cells from 2 B-ALL patients with the Philadelphia chromosome were similarly cultured, but in the presence of CD40-ligand and IL-4. After 4 days of culture, more than 58% of the ALL cells showed DC morphology and phenotype. The leukemic nature of the DC was validated by detection of the bcr-abl fusion gene in sorted DC populations by FISH. In functional studies, the leukemic DC were highly superior to the parental leukemic blasts for inducing allogeneic T-cell responses. Thus, CD34+ AML and ALL cells can be induced to differentiate into leukemic DC with morphologic, phenotypic, and functional similarities to normal DC.

Description: CD34+ hematopoietic stem cells from normal individuals and from patients with chronic myelogenous leukemia can be induced to differentiate into dendritic cells (DC). The aim of the current study was to determine whether acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) cells could be induced to differentiate into DC. CD34+ AML-M2 cells with chromosome 7 monosomy were cultured in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor  (TNF), and interleukin-4 (IL-4). After 3 weeks of culture, 35% of the AML-M2 cells showed DC morphology and phenotype. The DC phenotype was defined as upmodulation of the costimulatory molecules CD80 and CD86 and the expression of CD1a or CD83. The leukemic nature of the DC was validated by detection of chromosome 7 monosomy in sorted DC populations by fluorescence in situ hybridization (FISH). CD34+ leukemic cells from 2 B-ALL patients with the Philadelphia chromosome were similarly cultured, but in the presence of CD40-ligand and IL-4. After 4 days of culture, more than 58% of the ALL cells showed DC morphology and phenotype. The leukemic nature of the DC was validated by detection of the bcr-abl fusion gene in sorted DC populations by FISH. In functional studies, the leukemic DC were highly superior to the parental leukemic blasts for inducing allogeneic T-cell responses. Thus, CD34+ AML and ALL cells can be induced to differentiate into leukemic DC with morphologic, phenotypic, and functional similarities to normal DC.

Description: The concept of genetic randomisation has been applied to assess clinical outcomes between patients with hematological cancers treated with allografting or other therapies. Though not universally accepted, the comparison by the intention-to-treat principle between patients with HLA-identical siblings, who can be assigned to allografting, and those without, who cannot receive an allograft, is used as a surrogate for an unbiased randomisation. We previously published the results of a study where the treatment assignment of 162 newly diagnosed patients younger than 65 years was based only on the presence/absence of an HLA-identical sibling (Bruno et al, N Engl J Med). First-line treatment plans included a cytoreductive autograft followed by a nonmyeloablative allograft (Tandem auto-allo) or a second melphalan-based autograft (Double-auto). Primary endpoints were overall (OS) and event-free (EFS) survivals by intention-to-treat analysis. The 80 patients with a sibling donor were offered a Tandem auto-allo and the 82 without a Double-auto after high (140–200 mg/m2) or intermediate dose melphalan (100 mg/m2). After a median follow up of 45 (range 21–90) months, OS and EFS were significantly longer in patients with donors: 80 versus 54 months (p=0.01) and 35 versus 29 months (p=0.02). Median OS was not reached in the 58 (out of 60 enrolled, 97%) patients who completed Tandem auto-allo and was 58 months in the 46 (out of 59 enrolled, 78%) who completed high-dose double-auto (p=0.03). Here, we report a update analysis. At a median follow up of 56 months, OS was not reached for the 80 patients with an HLA-identical sibling and was 56 months for those without (HR 0.53, CI 95% 0.33–0.86, p=0.009). EFS remained significantly longer in patients with HLA-identical siblings: 35 versus 29 months (HR: 0.61; 95% Cl: 0.42–0.88, p=0.008). Median OS was not reached in the 58 patients who completed Tandem auto-allo and was 63 months in the 46 who completed high-dose double-auto (HR 0.47, CI 95% 0.25–0.86, p=0.016). EFS was 43 and 33 months (HR 0.64, CI 95% 0.40–1.02, p=0.06). By multivariate analysis, the presence of HLA-identical siblings was significantly correlated with longer OS and EFS. We carried out a stratified analysis, on the intent-to-treat population, that defined a patient subgroup at high risk in the light of high b -2-microglobulin levels or presence of del(13). The adjusted HRs by Cox models were 0.34 for OS and 0.52 for EFS similar to those obtained in the whole series. Though this exploratory analysis has low statistical power, its results indicate that del(13) does not offset the advantage in OS and EFS for patients with an HLA-identical sibling, but do not exclude an impact of del(13) in those patients undergoing an allograft. Attal et al. (N Engl J Med) previously reported median OS and EFS of 58 and 30 months, respectively, after double autologous transplantation, consistent with our results (OS: 63 months; EFS: 33 months). However, the EFS after Tandem auto-allo also indicates that long-term disease control is an issue. Allografting and new drugs with molecular targets should not be viewed as mutually exclusive. Thus, it is imperative to thoroughly explore their roles in increasing the response rates and their duration in Tandem auto-allo.

Description: Nonmyeloablative (NM) regimens extended the application of allogeneic transplantation (AT) to older and/or medically unfit patients ineligible for high-dose conditionings. Moreover, several patients are offered AT after failure of prior lines of therapy. We retrospectively evaluated 108 patients, median age 51 (16–67), with advanced or heavily pre-treated hematological cancers [19 acute myeloblastic (AML) and 1 lymphoblastic leukemia (ALL); 8 myelodysplastic syndrome (MDS); 9 chronic myeloid (CML) and 9 chronic lymphocitic leukemia; 3 myelofibrosis (MF); 48 myeloma beyond first line treatment; 8 Hodgkin’s and 8 non-Hodgkin’s lymphoma) who underwent NM-AT at 12 Italian transplant Centres. Median time between diagnosis and transplant was 20 months. Sixty-one% of patients had failed at least one prior line of therapy, including 36 refractory or relapsed patients after 1 or more autologous transplants. At allografting, 15 patients had disease at lower risk of relapse (AML and ALL in first complete remission (CR), MDS without blast excess, CML in first chronic phase, untreated MF). Forty-two patients had active disease. The comorbidity score was evaluated with an AT-specific comorbidity index (CI) as described by Sorror et al: 51 patients had CI=0, 42 CI=1–2 and 15 CI≥3. Patients were conditioned with fludarabine 90 mg/m2 and 2 Gy total body irradiation. GVHD prophylaxis consisted of cyclosporine and mycophenolate mophetile. Graft failure was observed in 1 patient and rejection after disease recurrence in 4. After a median follow-up of 28 months post-allografting, 58 (54%) had refractory/progressive disease and 36 (33%) were in CR, including 23 who were not in CR at transplant (p