Gottardo De Angelis

Haploidentical, unmanipulated, G-CSF–primed bone marrow transplantation for patients with high-risk hematologic malignancies

UNLABELLED Eighty patients with high-risk hematologic malignancies underwent unmanipulated, G-CSF–primed BM transplantation from an haploidentical family donor. Patients were transplanted in first or second complete remission (CR, standard-risk: n =45) or in > second CR or active disease (high-risk: n =35). The same regimen for GVHD prophylaxis was used in all cases. The cumulative incidence (CI) of neutrophil engraftment was 93% 0.1%. The 100-day CIs for II-IV and III-IV grade of acute GVHD were 24% 0.2% and 5% 0.6%, respectively. The 2-year CI of extensive chronic GVHD was 6% 0.1%. The 1-year CI of treatment-related mortality was 36% 0.3%. After a median follow-up of 18 months, 36 of 80 (45%) patients are alive in CR. The 3-year probability of overall and disease-free survival for standard-risk and high-risk patients was 54% 8% and 33% 9% and 44% 8% and 30% 9%, respectively. In multivariate analysis, disease-free survival was significantly better for patients who had standard-risk disease and received transplantations after 2007. We conclude that unmanipulated, G-CSF–primed BM transplantation from haploidentical family donor provides very encouraging results in terms of engraftment rate, incidence of GVHD and survival and represents a feasible, valid alternative for patients with high-risk malignant hematologic diseases, lacking an HLA identical sibling and in need to be urgently transplanted. KEY POINTS Haploidentical, unmanipulated, G-CSF-primed bone marrow transplantation. Haploidentical hematopoietic stem cell transplantation for hematologic malignancies.

Platelet gel for treatment of mucocutaneous lesions related to graft-versus-host disease after allogeneic hematopoietic stem cell transplant.

BACKGROUND: Platelet (PLT) gel has been successfully used in tissue regeneration of diabetic/surgical wounds through the releasing of growth factors such as basic fibroblast growth factor and PLT‐derived growth factor. Therefore, the PLT gel could represent a therapeutic tool in treating the deep and painful wounds sometimes occurring during graft‐versus‐host disease (GVHD).

Procalcitonin is a reliable marker of severe systemic infection in neutropenic haematological patients with mucositis

Patients with neutropenia are exposed to a high risk for infections in which fever is often the unique symptom [1]. Systemic infections remain the main cause of mortality in these patients therefore, the policy for infection management is to promptly administer empirical antibiotic therapy in order to avoid the increased risk of mortality related to the treatment delay [2]. However, microbiological diagnostic tests are not sufficiently rapid, sensitive or specific to indentify the microbial causes of fever, and a considerable number of patients suffer febrile episodes over a prolonged period without a definite microbiological etiology.

Minimal residual disease as biomarker for optimal biologic dosing of ARA-C in patients with acute myeloid leukemia

We assessed by flow cytometry minimal residual disease (MRD) in patients with acute myeloid leukemia (AML) given standard‐dose (SDAC) and high‐dose ARA‐C (HDAC) regimens. Of 163 patients enrolled, 130 (median age, 45 years; range, 18–59 years) qualified for analysis, all achieving complete remission after treatment with SDAC (n = 78) or HDAC (n = 52) plus etoposide and daunorubicin. Consolidation consisted of intermediate‐dose ARA‐C and daunorubicin. MRD negativity was significantly more frequent in the SDAC vs. HDAC arm after both induction (37% vs. 15%, P = 0.007) and consolidation (44% vs. 18%, P = 0.002). Respective median residual leukemic cell counts with SDAC and HDAC use were 1.5 × 10−3 and 4 × 10−3 (P = 0.033) after induction and 5.7 × 10−4 and 2.9 × 10−3 (P = 0.008) after consolidation. Based on ARA‐C schedule and post‐consolidation MRD status, the four patient groups (SDAC‐MRD−, HDAC‐MRD−, SDAC‐MRD+, and HDAC‐MRD+) displayed 5‐year overall survival rates of 60%, 33%, 24%, and 42% (P = 0.007), respectively, with 24%, 35%, 74%, and 48% (P < 0.0001) respective cumulative incidence of relapse estimates. MRD may serve as a biomarker for optimal biologic dosing of ARA‐C, and SDAC regimen appears to yield more frequent MRD negativity. Am. J. Hematol. 90:125–131, 2015.

Ponatinib Induces a Persistent Molecular Response and Graft-versus-Host Disease/Graft-versus-Leukemia Effect in a Patient with Philadelphia-Positive Acute Lymphoblastic Leukemia with a T315I Mutation following Early Relapse after Allogeneic Transplant

We describe the case of a patient with a Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL) treated with dasatinib plus steroids as the first-line therapy who achieved a molecular complete remission and then underwent a matched, unrelated donor allogeneic transplant. Five months after the transplant, he experienced a disease relapse with an T315I mutation, which was resistant to salvage chemotherapy. Once the details of the T315I mutation were acquired, we initiated ponatinib treatment at a standard dosage and observed a rapid decrease of minimal residual disease (MRD) at molecular assessment. The bone marrow evaluation after 2, 3, 6, 10 and 13 months was negative for MRD. After starting ponatinib, the patient experienced a skin graft-versus-host disease (GVHD), whereas no occurrence of GVHD was observed after transplant, suggesting that the efficacy of ponatinib could be related not only to the direct antileukemic effect, but also to its ability to promote an indirect graft-versus-leukemia effect. Ponatinib was well tolerated but a thyroid dysfunction mimicking a cardiovascular toxicity was observed and solved with hormonal substitutive treatment.

Bowel ultrasonography as an aid for diagnosis of intestinal acute graft-versus-host-disease after allogeneic haematopoietic stem cell transplantation.

OBJECTIVE Aim of our prospective study was to investigate accuracy of bowel ultrasonography in detecting gastrointestinal acute graft versus host disease (GVHD), when using clinical assessment as gold standard. In a subgroup of patients, bowel ultrasonography was compared with colonoscopy and histology in diagnosing of gastrointestinal acute GVHD. METHODS Fifty-two patients underwent allogeneic hematopoietic stem cell transplantation and developed gastrointestinal symptoms. RESULTS Clinical assessment lead to a diagnosis of gastrointestinal acute GVHD in 17/52 patients, no gastrointestinal acute GVHD was detected in 20/52 patients, while 15 patients were not able to complete the study. Bowel ultrasonography detected either bowel wall thickness of the ileum and the colon or dilation in 16/17 patients and showed 94% sensitivity (95% CI 0.69-0.99), 95% specificity (95% CI 0.73-0.99), and 94.5% accuracy. Colonoscopy was performed in 13/52 patients, showing gastrointestinal acute GVHD in 11/13. In these 11 patients, histology confirmed the diagnosis of gastrointestinal acute GVHD, and bowel ultrasonography detected findings compatible with gastrointestinal acute GVHD in all 11 patients, and was negative in the 2 patients with no gastrointestinal acute GVHD. CONCLUSION Bowel ultrasonography can be considered a valuable tool to add to clinical assessment for patients with suspected gastrointestinal acute GVHD for addressing a prompt and appropriate treatment.

Involvement of central nervous system in adult patients with acute myeloid leukemia: Incidence and impact on outcome

Incidence and effect on outcome of central nervous system (CNS) involvement in adult patients with acute myeloid leukemia (AML) is not clearly defined. To address this issue, 103 consecutive adult patients with newly diagnosed AML, regardless of neurologic symptoms, were submitted to a routine explorative lumbar puncture. Cerebrospinal fluid (CSF) samples were collected from 65 males and 38 females. All 103 CSF samples were examined by conventional cytology (CC) whereas 95 (92%) also by flow cytometry (FCM). At diagnosis, 70 patients (68%) were CNS negative (CNS-), whereas 33 (32%) were CNS positive (CNS+). In 11 of 33 (33%), CNS infiltration was documented either by CC or FCM , in 21 (67%) only by FCM. CNS positivity was significantly associated with a M4-M5 phenotype of the underlying AML (P = .0003) and with high levels of lactate dehydrogenase (P = .006). Overall, 80 of 103 (78%) achieved complete remission with no significant differences between CNS+ and CNS- patients. Five-year disease-free survival and overall survival were found to be shorter in CNS+ patients than in those CNS- (18% vs 50%, P = .006 and 19% vs 46%, P = .02, respectively). In multivariate analysis, CNS status and age were found to affect independently overall survival. In conclusion, the incidence of CNS involvement in adult patients with newly diagnosed AML is higher than expected. Regardless of neurologic symptoms, it should always be searched at diagnosis; CSF samples should routinely be investigated by FCM since a certain proportion of CNS involvements might remain undetected if examination is exclusively CC based.

The Rome Transplant Network model compared to the Italian Bone Marrow Donor Registry activity for unrelated donor search process and transplant efficiency for hematologic malignancy

From 2011 to 2014, a total of 71% of the 3834 patients with hematologic malignancies successfully identified a matched unrelated donor (MUD) through the Italian Bone Marrow Donor Registry (IBMDR), corresponding to a transplant efficiency of 62%.

Spontaneous bilateral kidney rupture during autologous stem cell transplantation in a patient affected by amyloidosis

Kidney spontaneous rupture is not a recognized complication neither for amyloidosis nor of autologous stem cell transplantation (ASCT). A 46-year-old white woman, affected by nephrotic syndrome, was diagnosed as AL amyloidosis by renal biopsy. We report the singular case of a bilateral spontaneous kidney rupture during ASCT for AL with renal rescue.

Epstein-Barr virus-positive lymphoma after alemtuzumab therapy for B-cell chronic lymphocytic leukemia.

B-cell chronic lymphocytic leukemia (B-CLL) is an indolent lymphoproliferative disorder with a progressive accumulation of small, morphologically mature B lymphocytes in the bone marrow, blood and lymphoid tissues. Alemtuzumab (MabCampath) is a IgG1 monoclonal antibody (mAb) that target the CD52 antigen, a glycosylated peptide highly expressed on B-CLL cells. This mAb is active in patients with B-CLL refractory to alkylating agents and purine nucleoside analogues. The primary adverse event so far reported is the induction of a profound and prolonged depletion of CD4 and CD8 subpopulations leading to an immunodeficient status and the development of opportunistic infections [1,2]. Recently, Epstein-Barr virus (EBV) related lymphoma have been reported in patients with T and B cell lymphoproliferative disorder after treatment with alemtuzumab [2–5]. Here, we report a case of an EBV related lymphoproliferative disorder secondary to alemtuzumab therapy for B-CLL. A 53 years old man diagnosed in January 1999 as having stage Rai II classical B-CLL, was admitted to our department in June 2007 as a consequence of disease progression. Analysis of IgVH mutational status was not performed. However, peripheral blood flow cytometry analysis revealed that tumor cells expressed ZAP-70, but were negative for CD38 expression. He was previously treated with two cycles of fludarabine 25 mg/m with no response. In March 2001, he received six doses of rituximab 375 mg/m obtaining a partial remission. In December 2005, because of disease progression associated with Coombs positive autoimmune hemolytic anemia (AHA) he was treated with rituximabþfludarabineþ cyclophosphamide (FCR) for six cycles obtaining a partial remission with resolution of the (AHA). From June 2007 to July 2007, he received 12 doses of alemtuzumab 30 mg/m, obtaining the clearance of bone marrow neoplastic cells with persistence of lymph nodes involvement. CD4 and CD8 levels prior alemtuzumab therapy were 517/mL and 1380/mL, respectively. After 4 weeks of anti CD52 therapy, treatment was interrupted because of CMV reactivation which was successfully treated with ganciclovir. In October 2007, the patient presented with fever AHA recrudescence and hepatomegaly. Laboratory analysis showed high LDH level (1299 UI/L), hypoalbuminemia (2.5 g/dL), elevated liver enzyme (ALT: 92 UI/L; AST: 87 UI/L) and anemia (Hb 8.4 g/dL). Lymphocyte count on peripheral blood was less than 40/mL. A CT scan revealed the presence of multiple enlarged lymph nodes at both sides of the diaphragm and liver enlargement. An abdominal ecography revealed multiple hypoechogenic liver lesions which were biopsied and showed large B cells CD20þ. In situ hybridisation for EBV-RNA was strongly positive and serum EBV DNA viral load showed more than 6500 copies/mL. Bone marrow evaluation didn’t show any infiltration by neoplastic cells. The diagnosis of stage IV CD20þ