Michele Malagola

Allogeneic transplantation improves the overall and progression-free survival of Hodgkin lymphoma patients relapsing after autologous transplantation: a retrospective study based on the time of HLA typing and donor availability

Hodgkin lymphoma relapsing after autologous transplantation (autoSCT) has a dismal outcome. Allogeneic transplantation (alloSCT) using reduced intensity conditioning (RIC) is a salvage option, but its effectiveness is still unclear. To evaluate the role of RIC alloSCT, we designed a retrospective study based on the commitment of attending physicians to perform a salvage alloSCT; thus, only Hodgkin lymphoma patients having human leukocyte antigen-typing immediately after the failed autoSCT were included. Of 185 patients, 122 found an identical sibling (55%), a matched unrelated (32%) or a haploidentical sibling (13%) donor; 63 patients did not find any donor. Clinical features of both groups did not differ. Two-year progression-free (PFS) and overall survival (OS) were better in the donor group (39.3% vs 14.2%, and 66% vs 42%, respectively, P < .001) with a median follow-up of 48 months. In multivariable analysis, having a donor was significant for better PFS and OS (P < .001). Patients allografted in complete remission showed a better PFS and OS. This is the largest study comparing RIC alloSCT versus conventional treatment after a failed autoSCT, indicating a survival benefit for patients having a donor.

Clinical efficacy and antiangiogenic activity of thalidomide in myelofibrosis with myeloid metaplasia. A pilot study

Increased neoangiogenesis has been reported in myelofibrosis with myeloid metaplasia (MMM). Thus we studied the effects of thalidomide, an antiangiogenic drug, in 12 MMM patients. Before treatment, all the cases showed a significantly increased micro-vessel density (MVD); in all eight tested cases bFGF and VEGF plasma levels were higher than controls. All patients presented disease progression in the last 3 months with standard therapy, regarding splenomegaly, anemia and/or thrombocytopenia and/or hyperleukocytosis. Thalidomide was administered at daily doses increasing from 100 to 600 mg. Eleven out of 12 patients were evaluable. No progression of disease was seen during the treatment in any case. In particular, spleen size decreased in 7/11 patients, anemia improved in 3/4 (two are now transfusion independent), thrombocytopenia in 2/2 and hyperleukocytosis in 2/5 patients. Side-effects were frequent, although not severe. After treatment, VEGF and bFGF plasma levels varied widely and in selected cases decreased. In particular, VEGF and/or bFGF decreased in 4/5 responders and in 1/3 non-responders. Moreover, MVD significantly decreased in all the responders evaluated after treatment. We conclude that thalidomide is a feasible therapy in MMM patients and looks promising at least to control the growth progression of disease.

Gemtuzumab Ozogamicin for Relapsed and Refractory Acute Myeloid Leukemia and Myeloid Sarcomas

Antibody-targeted chemotherapy is a promising approach in patients with hematological malignancies. In particular, gemtuzumab ozogamicin (GO, formerly CMA-676), an anti-CD33 antibody linked to calicheamicin, has been approved for the treatment of elderly patients with acute myeloid leukemia (AML) in relapse. Nevertheless, no data are until now available concerning the possible efficacy of GO for myeloid sarcomas (MS). We treated with GO 24 AML patients, in 5 cases presenting with myeloid sarcomas of the skin or bones. The overall complete response rate was 21%. The median duration of response was 6 months. Four out of the 5 patients with myeloid sarcoma showed a regression of the masses, in two cases also obtaining a clearance of marrow blasts. The most common adverse events included thrombocytopenia, neutropenia, infections, elevation of bilirubin and hepatic transaminases. Notably, severe bleeding occurred in 5 cases (21%). VOD was documented in 1 case. We conclude that GO is effective as a single agent in AML and myeloid sarcomas. Further data are required to clarify the possible correlation between GO administration and occurrence of bleeding.

Pulsed ATRA as single therapy restores long-term remission in PML-RARα-positive acute promyelocytic leukemia patients: real time quantification of minimal residual disease. A pilot study

All-trans retinoic acid (ATRA), alone or combined with chemotherapy (CHT) is widely used to induce complete remission (CR) in newly diagnosed acute promyelocytic leukemia (APL). If used alone, ATRA results in a substantial proportion of CRs. To maintain remission further, ATRA is commonly used with cycles of CHT, frequently followed by autologous (auto) or allogeneic (allo) stem cell transplantation (SCT), as early reports have shown that the continuous administration of ATRA as single therapy almost invariably leads to relapse in a short period of time (months). Pharmacokinetic studies have shown that induced resistance to ATRA is frequently suppressed by the intermittent use of the drug. In this study we applied an intermittent therapeutic protocol with ATRA in five APL patients who were either molecularly refractory after combined ATRA/CHT treatment, or relapsed, or at diagnosis, but not eligible for the combination treatment because of previous toxicity. They were treated with ATRA (45 mg/m2/day) for 21 days. The treatment was then prolonged continuously for 1 week every 2 weeks. Molecular analysis was performed by qualitative and quantitative reverse transcription-polymerase chain reaction (RT-PCR). All patients obtained molecular remission, as assessed by qualitative RT-PCR, in a median of 3 months (range 1–15). Quantitative RT-PCR confirmed these data, showing a progressive reduction (1 or 2 logs) to a ‘negligible quantity’ of PML-RARα fusion transcript (ratio PML-RARα/ABL × 104 ABL < 10−1) in all but one patient treated with pulsed ATRA therapy. These data were confirmed with qualitative and quantitative RT-PCR. After a median follow-up of 17 months from the start of ATRA therapy, 4/5 patients (80%) are in continuous complete molecular remission. To our knowledge, this is the first clinical observation that intermittent ATRA therapy (without chemotherapy) is effective not only in inducing but also in maintaining long-term molecular remission in APL patients. This approach could therefore be effective, if confirmed in larger series, in relapsed/refractory patients unsuitable for high-dose therapy and SCT; it may be proposed as induction therapy for selected older APL patients if considered not to be eligible for combined ATRA/CHT due to inadequate performance status or concurrent disease.

Kinetics of Th1/Th2 cytokines and lymphocyte subsets to predict chronic GVHD after allo-SCT: results of a prospective study.

The role of different cytokines and cells of immune system in the pathogenesis of chronic GVHD (cGVHD) is still controversial. Earlier studies, which were either retrospective or analysed one or a few factors, did not show unequivocal results. We prospectively evaluated cytokine levels and lymphocyte subsets in 30 patients who underwent Allo-SCT to investigate their possible correlation with cGVHD. Levels of IL-4, IL-6, IL-10, IFN-γ, tumour necrosis factor-alpha (TNF-α) and its soluble receptors were assessed by ELISA in 30 patients at different times after SCT. Lymphocyte subsets were evaluated by flow cytometry in peripheral blood at the same times as cytokines. A multivariate analysis was performed using principal component analysis and multi-factor ANOVA (analysis of variance). Eighteen patients developed cGVHD at a median time of 6 months (range, 5–9) after SCT. In multivariate analysis, we observed a correlation between cGVHD and clusters of cytokines and lymphocyte subsets from the third to the sixth month after SCT. These clusters changed their composition over time, but they constantly included natural killer (NK) and CD152+ T cells as negative predictors of cGVHD. TNF-α prevailed among other cytokines before the onset of cGVHD. This prevalence could be related partly to the defect of immunoregulatory cells.

Multicentre phase III trial on fludarabine, cytarabine (Ara-C), and idarubicin versus idarubicin, Ara-C and etoposide for induction treatment of younger, newly diagnosed acute myeloid leukaemia patients.

Fludarabine plus cytarabine (Ara‐C) and idarubicin (FLAI) is an effective and well‐tolerated induction regimen for the treatment of acute myeloid leukaemia (AML). This phase III trial compared the efficacy and toxicity of FLAI versus idarubicin plus Ara‐C and etoposide (ICE) in 112 newly diagnosed AML patients <60 years. Fifty‐seven patients received FLAI, as the first induction–remission course, and 55 patients received ICE. Post‐induction treatment consisted of high‐dose Ara‐C (HDAC). After HDAC, patients in complete remission (CR) received a second consolidation course (mitoxantrone, etoposide, Ara‐C) and autologous stem cell transplantation (auto‐SCT) or allogeneic (allo)‐SCT, according to the age, disease risk and donor availability. After a single induction course, CR rate was 74% in the FLAI arm and 51% in the ICE arm (P = 0·01), while death during induction was 2% and 9% respectively. Both haematological (P = 0·002) and non‐haematological (P = 0·0001) toxicities, especially gastrointestinal (i.e. nausea, vomiting, mucositis and diarrhoea), were significantly lower in FLAI arm. In both arms, relapses were more frequent in patients who were not submitted to allo‐SCT. After a median follow‐up of 17 months, 30% and 38% of the patients are in continuous CR in FLAI and ICE arm respectively. Our prospective randomised study confirmed the anti‐leukaemic effect and the low toxic profile of FLAI as induction treatment for newly diagnosed AML patients.

Prospective Phase II Study on 5-Days Azacitidine for Treatment of Symptomatic and/or Erythropoietin Unresponsive Patients with Low/INT-1–Risk Myelodysplastic Syndromes

Purpose: This phase II prospective study aimed to evaluate the efficacy and safety of 5-days azacytidine (5d-AZA) in patients with low-risk myelodysplastic syndromes (MDS). Second, single-nucleotide polymorphism (SNP) genetic profile and phosphoinositide-phospholipase C (PI-PLC) β1 levels were studied to evaluate possible biologic markers able to predict the hematologic response. Experimental Design: The study tested a lower intensity schedule of azacytidine. The treatment plan consisted of 75 mg/sqm/d subcutaneous administered for 5 days every 28 days, for a total of 8 cycles. Results: Thirty-two patients were enrolled in the study. The overall response rate was 47% (15 of 32) on intention-to-treat and 58% (15 of 26) for patients completing the treatment program. In this latter group, 5 (19%) achieved complete remission (CR) and 10 (38%) had hematologic improvement, according to the International Working Group (IWG) criteria. Three patients have maintained their hematologic improvement after 37, 34, and 33 months without other treatments. Moreover, 21 and 2 of 26 cases completing 8 cycles were transfusion-dependent for red blood cells and platelets at baseline, respectively. Of these, 7 (33%) and 2 (100%) became transfusion-independent at the end of the treatment program, respectively. Grade 3–4 neutropenia occurred in 28% of patients and 4 patients died early due to infections or hemorrhage. SNP results were not significantly correlated to the clinical outcome, whereas PI-PLCβ1 level anticipated either positive or negative clinical responses. Conclusions: 5d-AZA is safe and effective in a proportion of patients with low-risk MDS. PI-PLCβ1 gene expression is a reliable and dynamic marker of response that can be useful to optimize azacytidine therapy. Clin Cancer Res; 19(12); 3297–308. ©2013 AACR.

Fludarabine-based induction therapy does not overcome the negative effect of ABCG2 (BCRP) over-expression in adult acute myeloid leukemia patients

Over-expression of multidrug resistance (MDR) proteins PGP and BCRP has a negative prognostic impact in acute myeloid leukemia (AML) patients. Inclusion of fludarabine in induction chemotherapy increases remission rate in PGP over-expressing cases. We investigated the role of BCRP in 138 adult AML patients receiving induction therapy with fludarabine. None of the MDR-related proteins influenced complete remission attainment. Conversely, high levels of BCRP significantly affected disease-free survival, as higher relapse rates (48.5% vs 28.5%) and earlier relapse occurred in BCRP+ patients. Also overall survival was affected by BCRP positivity, and survival significantly worsened in case of concomitant PGP and BCRP over-expression.

Second chronic phase before transplantation is crucial for improving survival of blastic phase chronic myeloid leukaemia

Because successful outcome after transplantation seems to depend in acute myeloid leukaemia (AML) and in chronic phase chronic myeloid leukaemia (CML) on disease status at the time of transplantation, we investigated whether FLAN (fludarabine, cytosine arabinoside, mitoxantrone) induction before allogeneic stem cell transplantation (allo‐SCT) may be useful in blastic phase (BP)‐CML. Twenty patients with BP‐CML were studied: 10 patients received FLAN induction chemotherapy before proceeding to early allo‐SCT, whereas 10 patients were submitted to bone marrow transplantation (BMT) without remission induction. Eight out of 10 (80%) patients achieved second chronic phase after one course of therapy with FLAN and seven patients (six in second chronic phase and one with partial response) were then submitted to allo‐SCT. Of the six patients transplanted in the second chronic phase, all achieved molecular remission, four are still in second chronic phase, with intervals ranging from 10 to 54 months, whereas one patient died from infection having relapsed 14 months after SCT and one died of transplant‐related complications in the second chronic phase. Mean durations of second chronic phase and survival after allo‐SCT were both significantly longer than in the group of 10 BP‐CML patients submitted to allo‐SCT without FLAN remission induction treatment [22·4 (range 1–61) vs. 3·5 months (range 1–10) with FLAN and 22·7 (range 2–61) vs. 6·4 (range 1–16) months without FLAN]. We conclude that FLAN induction therapy followed by early allo‐SCT appears to be effective in the treatment of BP‐CML and could provide a curative possibility for BP‐CML patients.

Gemtuzumab-ozogamicin in combination with fludarabine, cytarabine, idarubicin (FLAI-GO) as induction therapy in CD33-positive AML patients younger than 65 years

INTRODUCTION The addition of gemtuzumab-ozogamicin (GO) to an induction regimen including synergistic drugs, such as intermediate dose of cytarabine (Ara-C), idarubicin and fludarabine (FLAI), could reduce treatment failure in acute myeloid leukemia (AML) patients. Nevertheless, the role and safety of this antibody target-therapy in first-line chemotherapy in patients younger than 65 years has not yet been defined. PATIENTS AND METHODS The primary goal of this prospective phase II pilot study was to evaluate the efficacy and the safety profile of FLAI plus GO as induction regimen. Thirty consecutive AML patients were included. All patients were younger than 65 with a median age of 53 years and CD33 expression exceeded 20% in all cases. The M/F ratio was 16/14 and 21/30 (70%) of patients were poor-risk at diagnosis. The induction regimen (FLAI-GO) included fludarabine (30mg/m(2)) and Ara-C (2g/m(2)) on days 1-5, idarubicin (10mg/m(2)) on days 1, 3, and 5 and GO (3mg/m(2)) on day 6. Hematopoietic stem cell transplant (HSCT) was planned for all high risk AML patients in first complete remission (CR) after consolidation with intermediate doses of Ara-C and idarubicin (IDAC-IDA). Cytogenetic, multidrug-resistance phenotype, FLT3 mutation status, and WT1 quantitative expression analyses were performed at diagnosis in all patients. WT1 expression and cytogenetic (in positive cases) analyses were performed after induction to detect and follow minimal residual disease. RESULTS Patients were evaluated for response rate, treatment-related adverse events, overall survival and relapse free survival. After induction with FLAI-GO, CR rate was 90% (26 of 29 evaluable pts); one patient achieved partial remission and two were resistant. There was only one case of death during induction (DDI). After FLAI-GO, the mean value of WT1 dropped from 4200+/-2777 copies/10(4)ABL to 192+/-399 copies/10(4)ABL. The toxicity of FLAI-GO was acceptable; 57% of patients experienced transient and reversible GO infusion-related adverse events (especially fever and chills), but no cases of veno-occlusive disease occurred during CHT or after HSCT. After a median follow-up of 16 months (range 2-25), 24/30 (80%) patients are alive (24/24 in CR). The probability of 1-year OS and RFS was 90 and 85%, respectively. Allogeneic and autologus HSCT was performed in 19 (63%) and 4 (13%) patients, respectively. CONCLUSIONS These preliminary results suggest that FLAI-GO is an effective and well tolerated induction regimen for CD33 positive AML patients younger than 65 years, with a high complete response rate, favourable safety profile, low DDI. These results encourage the testing of this regimen in a multicenter prospective trial.