Bortezomib Plus Dexamethasone Followed by Escalating Donor Lymphocyte Infusions for Patients with Multiple Myeloma Relapsing or Progressing after Allogeneic Stem Cell Transplantation

Abstract 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

Multicenter Experience Using Total Lymphoid Irradiation and Antithymocyte Globulin as Conditioning for Allografting in Hematological Malignancies

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

Italian real life experience with ibrutinib: Results of a large observational study on 77 relapsed/refractory mantle cell lymphoma

Although sometimes presenting as an indolent lymphoma, mantle cell lymphoma (MCL) is an aggressive disease, hardly curable with standard chemo-immunotherapy. Current approaches have greatly improved patients' outcomes, nevertheless the disease is still characterized by high relapse rates. Before approval by EMA, Italian patients with relapsed/refractory MCL were granted ibrutinib early access through a Named Patient Program (NPP). An observational, retrospective, multicenter study was conducted. Seventyseven heavily pretreated patients were enrolled. At the end of therapy there were 14 complete responses and 14 partial responses, leading to an overall response rate of 36.4%. At 40 months overall survival was 37.8% and progression free survival was 30%; disease free survival was 78.6% at 4 years: 11/14 patients are in continuous complete response with a median of 36 months of follow up. Hematological toxicities were manageable, and main extra-hematological toxicities were diarrhea (9.4%) and lung infections (9.0%). Overall, 4 (5.2%) atrial fibrillations and 3 (3.9%) hemorrhagic syndromes occurred. In conclusions, thrombocytopenia, diarrhea and lung infections are the relevant adverse events to be clinically focused on; regarding effectiveness, ibrutinib is confirmed to be a valid option for refractory/relapsed MCL also in a clinical setting mimicking the real world

Autologous Stem Cell Transplantation in Multiple Myeloma: Where Are We and Where Do We Want to Go?

The introduction of high-dose therapy in the 1990s as well as the development of drugs such as thalidomide, lenalidomide, and bortezomib in the 2000s led to an impressive improvement in outcome of patients with multiple myeloma (MM) eligible for autologous stem cell transplantation (ASCT). Clinical trials conducted in the first ten years of the twenty-first century established as standard therapy for these patients a therapeutic approach including induction, single or double ASCT, consolidation, and maintenance therapy. More recently, incorporating second-generation proteasome inhibitors carfilzomib and monoclonal antibody daratumumab into each phase of treatment significantly improved the efficacy of ASCT in terms of measurable residual disease (MRD) negativity, Progression Free Survival (PFS), and Overall Survival (OS). The availability of techniques such as multiparameter flow cytometry (MFC) and next-generation sequencing (NGS) for MRD assessment allowed the design of MRD-based response-adjusted trials that will define, in particular, the role of consolidation and maintenance therapies. In this review, we will provide an overview of the most recent evidence and the future prospects of ASCT in MM patients

Low-dose Gemtuzumab-Ozogamicin as post-consolidation therapy in elderly patients with acute myeloid leukaemia: a pilot study.

The incidence of acute myeloid leukemia (AML) increases with advancing age, and in older patients the chance of cure has not substantially improved recently. In the elderly the incidence of secondary AML is high, and is often associated with both high- risk cytogenetic abnormalities and expression of the multidrug resistance protein (MDR1) and p-glycoprotein (p-gp), both of which are associated with poor outcomes (Appelbaum et al, 2006). Gemtuzumab-Ozogamicin (GO) is a humanized anti-CD33 monoclonal antibody conjugated to Calicheamicin that is rapidly internalized after binding to CD33. GO seems to be more selective than conventional chemotherapy, as CD33 is expressed on AML cells but not in normal haematopoietic stem cells (SCs) or in non-haematopoietic tissues (Sievers et al, 2001). In a series of phase II studies including 142 patients with AML in first relapse, GO monotherapy was associated with a 30% overall complete remission (CR) rate, including a 26% rate in patients over 60 years of age (Sievers et al, 2001; Larson et al, 2002). These results led to US Food and Drug Administration approval of GO for the treatment of patients over 60 years with relapsed AML (Bross et al, 2001). As a consequence of these results, there is interest in extending the use of GO to a frontline treatment for AML in combination with conventional chemotherapy. Little is known about the usefulness of GO as consolidation and/or maintenance therapy, and no data on the topic have been published to date. In particular, there are no data concerning the safety and efficacy of GO in the setting of post-consolidation therapy in AML patients except for a short report concerning the effects after autologous stem cell transplantation (ASCT) (Cascavilla et al, 2008). GO mono- therapy has typically been administered as a 2-h infusion at a dose of 9 mg/m2 on days 1 and 15 of treatment, but the administration of fractionated doses has recently been reported to have a better safety profile (Taksin et al, 2007). We evaluated the efficacy of low-dose GO as late consolidation therapy after CR in a subset of fit elderly patients who were enrolled in a prospective study. From June 1999 to December 2007, 125 patients of 60 years of age or older with morphologically-confirmed AML and non-acute promyelocytic leukaemia were observed in our institution. The preliminary results from 42 patients were reported in 2007 (Olivieri et al, 2007). Fit patients, selected according to previously published inclusion criteria (Olivieri et al, 2007), were treated with intensive chemotherapy, followed by SC mobilization and ASCT (Olivieri et al, 2007). Patients who successfully mobilized SCs underwent ASCT, while poor mobilisers received a further consolidation including standard chemotherapy or investigational immunotherapy with GO. Among the initial 125 patients, 79 fulfilled the inclusion criteria; of those, 56 (72Æ1%) achieved CR, and 52 received the first intensive consolidation course followed by G-CSF to collect SC for ASCT. In cases of mobilisation failure, patients were allowed to chose between an experimental approach B J H 8 1 6 8 B Dispatch: 8.3.10 Journal: BJH CE: Varun Kumar Journal Name Manuscript No. Author Received: No. of pages: 3 PE: Subhashree Table I. Clinical and biological characteristics of the three groups of patients receiving consolidation with GO (A), ASCT (B), Chemo- therapy (CHT) (C) and Allogeneic Transplantation (D). A (%) B (%) C (%) D (%) P Gender Male 8 (62) 8 (42Æ1) 3 (50) 3 (60) N.S. Female 5 (38) 11 (57Æ9) 3 (50) 2 (40) Age (years) Median = 70 (range, 61–76) £70 7 (54) 10 (52Æ6) 5 (83Æ3) 4 (80) N.S. >70 6 (46) 9 (47Æ4) 1 (16Æ7) 1 (20) FAB subtype M0 0 5 (26Æ5) 0 0 N.S. M1 3 (23) 4 (21) 2 (33Æ3) 2 (40) M2 3 (23) 8 (42) 4 (66Æ7) 2 (40) M4 3 (23) 2 (10Æ5) 0 1 (20) M5 3 (23) 0 0 0 M6 1 (8) 0 0 0 M7 0 0 0 0 Leucocytosis (·109/l) WBC <10 8 (61Æ5) 9 (47Æ4) 4 (66Æ7) 4 (80) N.S. WBC 10–50 5 (38Æ5) 6 (31Æ6) 1 (16Æ7) 1 (20) WBC >50 0 4 (21) 1 (16Æ7) 0 Karyotype Poor 2 (15Æ4) 7(36Æ8) 1 (16Æ7) 4 (80) N.S. Intermediate 6 (46Æ2) 8 (42Æ1) 4 (66Æ7) 0 Favourable 2 (15Æ4) 0 1 (16Æ7) 1 (20) NE 3 (15Æ4) 4 (21Æ1) 0 0 Secondary disease* Yes 3 (23) 8 (42) 2 (33Æ3) 1 (20) N.S. No 10 (77) 11 (58) 4 (66Æ7) 4 (80) FAB, French-American-British classification; NE, not evaluated; WBC, white blood cell. *To chemotherapy or Myelodysplastic Syndrome. correspondence ª 2010 Blackwell Publishing Ltd, British Journal of Haematology doi:10.1111/j.1365-2141.2010.08168.x 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 including low-dose GO or a further conventional consolidation course. GO was administered on a compassionate basis, and the costs were charged to our department. Among the 52 patients who received intensive consolidation, two died and seven relapsed; thus, 43 patients were evaluable for post-remission treatment after the SC mobilization attempt. Of those, 19 patients (44%) successfully mobilized SC and received ASCT. Of the 24 that did not mobilise SC, 13 received GO, six patients refused GO and received a second consolidation with chemo- therapy, and five patients received reduced intensity conditioning allogeneic transplant from sibling donors. The current analysis did not include all patients receiving allogeneic transplant because of the poor prognosis of the disease. The disease characteristics of the remaining patients were equally distributed in the three groups, and the data are shown in Table I. All the patients received GO at a dose of 3 mg/m2 three times monthly on an outpatient basis and received common antimicrobial prophylaxis. No patients needed hospitalisation for infections or other major toxicities; the median duration of neutropenia (PMN <0Æ5 · 109/l) after GO was 12 d (range 0–33 d). The main toxicities (World Health Organization grade III–IV) were myelosuppression (n = 9), hypertransam- inasaemia (n = 1) and anaphylaxis (n = 3); no major unex- pected adverse events were observed. With a median follow up of 58 months (range 19–89), a total of 15 patients were alive and in CR: five received ASCT (median follow-up 77 months, range 45-89), nine received GO (median follow-up 38 months, range: 19–75 months), and one, who received chemotherapy, has been followed for 72 months. Two patients receiving GO relapsed and eventually died after 13 and 19 months from CR after the first consolidation. Two more patients relapsed after 15 and 32 months after a second CR after salvage chemother- apy, followed by three doses of GO 3 mg/m2 administered as consolidation therapy. In conclusion, nine of the 13 patients who received GO as late consolidation therapy were alive and in continuous CR (including two patients with secondary AML and two with a complex karyotype). The Landmark survival analysis showed better overall survival (OS) and disease-free survival (DFS) (P = 0Æ017 and 0Æ01 respectively) in the 13 patients that received GO (5-year OS, 60%; 5-year DFS, 67%) compared with patients that received either ASCT (5-year OS and DFS: 26%) or chemotherapy (5-year OS and DFS: 17%) (Fig 1). Our preliminary data support a potential role for low-dose GO in consolidation therapy in elderly patients with AML who are able to achieve CR after intensive induction. Late consolidation with low-dose GO seems to be safe and easily manageable; the myelosuppression was relevant, but generally short. All patients received the 3 GO infusions on an outpatient basis without further readmissions and without fatal events. These preliminary data encourage the use of low-dose GO as late consolidation therapy to eliminate the minimal residual disease (MRD) in older patients with AML. Larger studies are needed for confirmation, possibly including monitoring of MRD during treatment. It also remains to be established if SC collection failure after CR represents an independent favour- able prognostic factor in AML patients, as suggested by some retrospective data (Keating et al, 2003). Antonella Poloni1 Debora Capelli1 Silvia Trappolini1 Benedetta Costantini1 Mauro Montanari1 Guido Gini1 Ilaria Scortechini1 Giorgia Mancini1 Giancarlo Discepoli2 Pietro Leoni1 Attilio Olivieri3 1Dipartimento di Scienze Mediche e Chirurgiche, Sezione di Ematologia, Universita` Politecnica delle Marche and Azienda Ospedaliera Ospedali Riuniti, 2Laboratorio di Citogenetica e Genetica Molecolare, Clinica di Pediatria, Ospedali Riuniti, Ancona, and 3Azienda Ospedaliera San Carlo, Potenza, Italy. E-mail: [email protected] 0 20 40 60 80 100 0 12 24 36 48 60 72 84 96 Cumulative probability (%) Months OS GO ASCT CHT 0 20 40 60 80 100 0 12 24 36 48 60 72 84 96 Cumulative probability (%) Months DFS Fig 1. Comparison of the outcome (OS and DFS) of patients receiving late consolidation with Gemtuzumab-Ozogamicin (GO), autologous stem cell transplantation (ASCT) or chemotherapy (CHT) (log rank test). Correspondence 2 ª 2010 Blackwell Publishing Ltd, British Journal of Haematology 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 References Appelbaum, F.R., Gundacker, H., Head, D.R., Slovak, M.L., Willman, C.L., Godwin, J.E., Anderson, J.E. & Petersdorf, S.H. (2006) Age and acute myeloid leukaemia. Blood, 107, 3481–3485. Bross, P.F., Beitz, J., Chen, G., Chen, X.H., Duffy, E., Kieffer, L., Roy, S., Sridhara, R., Rahman, A., Williams, G. & Pazdur, R. (2001) Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia. Clinical Cancer Research, 7, 1490–1496. Cascavilla, N., D’Arena, G., Greco, M.M., Melillo, L., Merla, E. & Carella, A.M. (2008) Gemtuzumab-Ozogamicin as maintenance therapy after Autologous Stem Cell Transplantation in elderly patients with Acute Myeloid Leukaemia. British Journal of Haematology , 142, 852–853. Keating, S., Suciu, S., de Witte, T., Zittoun, R., Mandelli, F., Belhabri, A., Amadori, S., Fibbe, W., Gallo, E., Fillet, G., Varet, B., Meloni, G., Hagemeijer, A., Fazi, P., Solbu, G., Willemze, R., EORTC Leukemia Group & GIMEMA Leukemia Group. (2003) The stem cell mobilizing capacity of patients with acute myeloid leukemia in complete remission correlates with relapse risk: results of EORTC- GIMEMA AML 10 trial. Leukemia, 17, 60–67. Larson, R.A., Boogaerts, M., Estey, E., Karanes, C., Stadtmauer, E.A., Sievers, E.L., Mineur, P., Bennett, J.M., Berger, M.S., Eten, C.B., Munteanu, M., Loken, M.R., Van Dongen, J.J., Bernstein, I.D., Appelbaum, F.R. & Mylotarg Study Group. (2002) Antibody- targeted chemotherapy of older patients with acute myeloid leukemia in first relapse using Mylotarg (gemtuzumab ozogamicin). Leukemia, 16, 1627–1636. Olivieri, A., Capelli, D., Troiani, D., Poloni, A., Montanari, M., Offidani, M., Discepoli, G. & Leoni, P. (2007) A new intensive induction schedule, including high-dose Idarubicin, high-dose Aracytin and Amifostine, in older AML patients: feasibility and long-term results in 42 patients. Experimental Hematology, 35, 1074–1082. Sievers, E.L., Larson, R.A., Stadtmauer, E.A., Estey, E., Lo¨wenberg, B., Dombret, H., Karanes, C., Theobald, M., Bennett, J.M., Sherman, M.L., Berger, M.S., Eten, C.B., Loken, M.R., Van Dongen, J.J., Bernstein, I.D., Appelbaum, F.R. & Mylotarg Study Group. (2001) Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukemia in first relapse. Journal of Clinical Oncology, 19, 3244–3254. Taksin, A.L., Legand, O., Raffoux, E., de Revel, T., Thomas, X., Con- tenin, N., Bouabdallah, R., Pautas, C., Turlure, P., Reman, O., Gardin, C., Varet, B., de Botton, S., Pousset, F., Farhat, H., Chevret, S., Dombret, H. & Castaigne, S. (2007) High efficacy and safety profile of fractionated doses of Mylotarg as induction therapy in patients with relapsed acute myeloblastic leukemia: a prospective study of the alfa group. Leukemia, 21, 66–71. Keywords: AML, chemotherapy,

Gemtuzumab-Ozogamicin as Post-Consolidation Therapy In Elderly Patients with Acute Myeloid Leukemia: a Pilot Study

none12Debora, Capelli; Mancini, Giorgia; Chiarucci, Martina; Saraceni, Francesco; Poloni, Antonella; Trappolini, Silvia; Costantini, Benedetta; Montanari, Mauro; Gini, Guido; Scortechini, Ilaria; Leoni, Pietro; Olivieri, AttilioDebora, Capelli; Mancini, Giorgia; Chiarucci, Martina; Saraceni, Francesco; Poloni, Antonella; Trappolini, Silvia; Costantini, Benedetta; Montanari, Mauro; Gini, Guido; Scortechini, Ilaria; Leoni, Pietro; Olivieri, Attili