Atelda Romano

Prolonged molecular remission in advanced acute promyelocytic leukaemia after treatment with gemtuzumab ozogamicin (Mylotarg CMA-676).

We report a patient with acute promyelocytic leukaemia (APL) who received two doses of gemtuzumab ozogamicin for advanced disease. Previous treatments included front‐line all‐trans retinoic acid and anthracyclines, polychemotherapy consolidation, salvage chemotherapy for the first relapse followed by autologous stem cell transplantation (ASCT), arsenic trioxide for the second relapse followed by a second ASCT and then high‐dose methotrexate for more advanced systemic disease with central nervous system involvement. The patient achieved prolonged haematological and molecular remission after monotherapy with gemtuzumab ozogamicin given at the time of the third relapse.

Early detection of meningeal localization in acute promyelocytic leukaemia patients with high presenting leucocyte count

Summary. Extramedullary relapse occurs infrequently in acute promyelocytic leukaemia (APL) but has been increasingly reported after the advent of all‐trans retinoic acid (ATRA) treatment, probably as a consequence of improved patient survival. We describe our single centre experience of six APL patients who had disease localization in the central nervous system (CNS). In three patients, clinical symptoms (headache and/or nausea) that presented during follow‐up led to the performance of a lumbar puncture and detection of overt CNS infiltration. Two of these patients had simultaneous haematological relapse and one was in molecular remission when CNS leukaemia was documented. One patient with no local symptoms showed CNS infiltration at the time of molecular relapse. Following the introduction of routine lumbar puncture, carried out after front‐line induction in all newly diagnosed patients with white blood cell count (WBC) greater than 10 × 109/l, two additional patients in molecular remission with no local symptoms were found to have initial APL localization in the CNS. Presenting features included in 6/6 patients an elevated WBC count (> 10 × 109/l) and a predominance of the PML/RAR bcr3 type (5/6 patients) and of microgranular morphology (5/6 patients). Our findings highlight the importance of carrying out lumbar puncture in APL patients presenting with high‐risk features.

Allogeneic stem cell transplantation for advanced acute promyelocytic leukemia: results in patients treated in second molecular remission or with molecularly persistent disease

In all, 17 consecutive patients in hematological complete remission (HCR) of acute promyelocytic leukemia (APL) received allogeneic stem cell transplantation (SCT) from an HLA-identical sibling and were monitored by reverse transcriptase polymerase chain reaction of PML/RARα prior and after transplant. Median age was 31 years (range 3–50 years). At 10 years, the actuarial probabilities of nonrelapse mortality, relapse and disease-free survival were 32% (95% CI: 8–56%), 33% (95% CI: 6–60%) and 46% (95% CI: 22–70%). Six patients tested PCR +ve (1st HCR n=2; 2nd HCR n=3; 3rd HCR n=1) and 11 PCR −ve (2nd HCR n=11) pre-SCT. Of the six patients PCR +ve, two showed early persistence of PCR positivity and converted to sustained PCR negativity after CSA withdrawal (one died of secondary tumor in molecular remission and one is alive in relapse), while four converted to PCR −ve rapidly (one died of the underlying disease and three are in molecular remission). Of the 11 patients PCR −ve pre-SCT, six died (four of transplant-related mortality, one of relapse and one after heart transplantation) and five are alive, four in molecular remission and one is in relapse. Allogeneic SCT seems a valid option for advanced APL, particularly for the poor prognostic group of patients with pre-SCT molecularly persistent disease.

Pre-transplant prognostic factors for patients with high-risk leukemia undergoing an unrelated cord blood transplantation

Summary:From July 1995 to December 2001, 42 patients with leukemia aged 1–42 years underwent cord blood transplant (CBT) from unrelated, ⩽2 antigen HLA mismatched donors. In all, 26 patients were in ⩽2nd complete remission and 16 in more advanced phase. Conditioning regimens, graft-versus-host disease (GVHD) prophylaxis and supportive policy were uniform for all patients. The cumulative incidence of engraftment was 90% (95% CI: 0.78–0.91). The cumulative incidence of III–IV grade acute- and chronic-GVHD was 9% (95% CI: 0.04–0.24) and 35% (95% CI: 0.21–0.60), respectively. The 4-year cumulative incidence of transplant-related mortality (TRM) and relapse was 28% (95% CI: 0.17–0.47) and 25% (95% CI: 0.14–0.45), respectively. The 4-year overall survival (OS), leukemia-free survival (LFS) and event-free survival (EFS) were 45% (95% CI: 0.27–0.63), 47% (95% CI: 0.30–0 .64) and 46% (95% CI: 0.30–0.62), respectively. In multivariate analysis, the most important factor affecting outcomes was the CFU-GM dose, associated with CMV serology (P=0.003 and 0.04, respectively) in influencing OS and with patient sex (P=0.008 and 0.03, respectively) in influencing LFS. Finally, CFU-GM dose was the only factor that affected EFS significantly (P=0.02). In conclusion, the infused cell dose expressed as in vitro progenitor cell growth is highly predictive of outcomes after an unrelated CBT and should be considered the main parameter in selecting cord blood units for transplant.

Ear involvement in acute promyelocytic leukemia at relapse: a disease-associated 'sanctuary'?

Extramedullary (EM) involvement occurs infrequently in acute promyelocytic leukemia (APL) and usually involves skin and CNS. We describe seven patients (four observed at a single institution) who relapsed in various sites of the auditory apparatus, including the external canal and middle ear (temporal bone). Front-line treatment included ATRA and chemotherapy (six patients) or chemotherapy alone (one patient). Three patients had concomitant hematologic relapse, two had molecular relapse and two were in hematologic and molecular remission when ear localization was documented. Local symptoms that stimulated further diagnostic studies included ear bleeding/discharge in the first patient, but were mild in the others (hypoacusia, five patients; earache, two patients). Ear involvement by leukemia was documented by histological and/or molecular studies after local surgery in five cases, and by CT scan or NMR in the remaining patients. We suggest that the ear might represent a specific sanctuary for disease involvement in APL.

CD34+ cell mobilization for allogeneic progenitor cell transplantation: efficacy of a short course of G-CSF

BACKGROUND: G–CSF‐mobilized PBPCs are considered the richest source of HPCs for both autologous and allogeneic transplantation, but, despite their wide use, the best dose and schedule for G–CSF administration have not been definitively established.

Umbilical cord blood transplant from unrelated HLA-mismatched donors in children with high risk leukemia

In the last 3 years, 14 children with high-risk leukemia (11 ALL, 2 AML and 1 CML) underwent cord blood transplantation from unrelated HLA-mismatched donors at a median of 99 days from the start of search. Eight patients were transplanted in second CR, one in accelerated phase, three at relapse and two patients in first CR. Conditioning regimen (fractionated TBI, etoposide, CY and anti-lymphocyte serum) and prophylaxis of GVHD (CsA and 6-methylprednisolone) were identical for all patients. Neutrophils > 0.5 × 109/l were reached at a median of 33 days from transplant, but in four cases we observed an autologous hematopoietic reconstitution (three spontaneous, one after autologous BM rescue). Acute and chronic GVHD were observed in 10/14 and 3/8 evaluable cases, respectively. Three patients died of transplant-related toxicity and three patients relapsed. The probabilities of event-free, disease-free and overall survival were 50, 53 and 64%, respectively. Cord blood transplant from HLA-mismatched unrelated donor is a valid option for the treatment of children with high-risk leukemia. With our eligibility criteria, conditioning regimen and prophylaxis of graft-versus-host disease, the main obstacles to successful transplant were represented by graft failure and fatal acute GVHD.

Cytomegalovirus reactivation after autologous stem cell transplantation in myeloma and lymphoma patients: A single-center study

AIM To determine the incidence of and the risk factors for cytomegalovirus (CMV) symptomatic infection and end-organ disease after autologous stem cell transplantation (ASCT). METHODS A total of 327 consecutive non CD34(+) selected autografts performed from the Hematology and Stem Cell Transplantation Unit of Regina Elena National Cancer Institute of Rome (Italy) in the period comprised between January 2003 to January 2015, were reviewed. Over the 327 autografts, 201 were performed in patients with multiple myeloma, whereas the remaining 126 in patients affected by non-Hodgkins lymphoma and Hodgkins lymphoma. The patients who underwent an ASCT for an acute leukemia (n = 20) in the same period were excluded from this analysis. CMV DNA load in the blood has been determined by polymerase-chain reaction in the case of a clinical suspicion of reactivation, therefore, no routine monitoring strategy was adopted. In the presence of signs and symptoms of CMV reactivation an antiviral treatment was performed. RESULTS Overall, 36 patients (11%) required a specific antiviral treatment for a symptomatic CMV reactivation (n = 32) or an end-organ disease (n = 4). We observed 20 and 16 cases of CMV reactivation among lymphoma (16%) and myeloma patients (8%), respectively. Among cases of end-organ disease, 3 were diagnosed as interstitial pneumonia and one remaining case as hemorrhagic enteritis. All cases of CMV reactivation were observed in IgG seropositive patients, with no documented cases of primary CMV infection. All patients were treated with a specific antiviral therapy, with a global rate of hospitalization of 55%; four patients received intravenous immunoglobulins. Transplant-related mortality was significantly higher in patients who experienced a CMV reactivation (8.4% ± 4.7% vs 1.7% ± 0.8%; P = 0.047). In univariate analysis, a pre-transplant HBcIgG seropositivity, a diagnosis of T-cell non-Hodgkins lymphoma and higher median age at transplant were significantly associated with the risk of developing a clinically relevant CMV infection requiring specific antiviral therapy (P < 0.001, P = 0.042 and P = 0.004, respectively). In multivariate analysis, only a pre-transplant HBcIgG seropositivity (OR = 8.928, 95%CI: 1.991-33.321; P = 0.023) and a diagnosis of T-cell non-Hodgkins lymphoma (OR = 4.739, 95%CI: 1.511-11.112; P = 0.042) proved to be independent predictors of a post-transplant clinically relevant CMV reactivation. CONCLUSION A symptomatic CMV infection can occur in about 11% of adult patients with lymphoma or myeloma undergoing ASCT. A pre-transplant HBcIgG seropositivity and a diagnosis of T-cell non-Hodgkins lymphoma should be considered as independent predictor factors of CMV reactivation.

Flow cytometry characterization in central nervous system and pleural effusion multiple myeloma infiltration: an Italian national cancer institute experience

Extramedullary relapse of multiple myeloma (MM) can occur in some patients, particularly after a long history of disease. However, central nervous system (CNS) and pleural effusion (PE) malignant myelomatosis, characterized by cerebrospinal fluid (CSF) and PE infiltration by tumour plasma cells (PC) are very rare, accounting for less than 1% of MM patients. The diagnosis of CNS and PE myelomatosis is historically based on PC detection by cytology. Multiparameter flow cytometry (FCM) has recently been shown to be a powerful technique for both diagnosis and minimal residual disease identification in myeloma patients (Paiva et al, 2009; Rawstron et al, 2013). However, to date, there is limited published experience regarding the use of FCM for the diagnosis of CNS and PE myelomatosis (Marini et al, 2014; Keklik et al, 2012). In this report, we describe clinical and biological features of six MM patients with CNS or PE myelomatosis diagnosed by FCM (Table I). Erythrocyte-lysed bone marrow (BM), peripheral blood (PB), CSF and PE samples were processed and stained using a six-colour panel (FITC/PE/PerCP/ PE-Cy7/APC/APC-Cy7) and the ‘Duo-lyse’ program of the Becton Dickinson Bioscience (BDB, Milan, Italy) Lyse-WashAssistant according to the following combinations: (i) CD28/ CD138/CD45/CD38/CD33/CD20; (ii) CD38/CD138/CD45/ CD56/CD117/CD19. The PC surface phenotype aberrancies were used as patient-specific disease markers (PSDM) to document intra-cytoplasm immunoglobulin (cy-Ig) light chains restriction: (iii) cy-Igk/cy-Igj/CD19/CD38/anti-PSDM/CD45 and the Cytofix & Cytoperm technique according to manufacturer’s recommendations. All antibodies were from BDB except CD28, CD33 and CD138 (Beckman Coulter, Milan, Italy). A minimum of 1 9 10 CD138/CD38 bright PC were acquired and analysed in all but one PB sample from Patient 5 (Table II) utilizing a BDB FACSCanto flow cytometer with FACSDiva software. A j/kratio <0 5 or >4 0, evaluated on CD19-positive or CD19negative/PSDM-positive PC, was used to discriminate between normal and neoplastic PC. Table I shows the relevant clinical features of the six patients. Three patients presented a CNS myelomatosis after one or more chemotherapeutic lines including novel agents, autologous and allogeneic haematopoietic stem cell transplantation. These three patients presented neurological signs and symptoms. In particular, one patient presented nausea, vomiting, confusion and headache; the second had cervical discomfort with first and second cervical vertebra body lesions and the third had headache with disturbance of the speech, in association with a neoplastic jaw mass. In two patients PE myelomatosis was documented at disease progression after one or two chemotherapeutic lines with novel agents, presented as progressive dyspnea. Finally, a very aggressive disease relapse with concomitant CNS and PE myelomatosis was documented in one patient after induction

Comparison between biosimilar filgrastim vs other granulocyte‐colony stimulating factor formulations (originator filgrastim, peg‐filgrastim and lenograstim) after autologous stem cell transplantation: a retrospective survey from the Rome Transplant Network

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