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Systemic amyloidosis arises from monoclonal CD38+ plasma cells that produce misfolded immunoglobulin light chains, which form amyloid fibrils that are deposited into different tissues, leading to organ damage. Daratumumab is a human IgG/k monoclonal antibody that targets CD38, a glycoprotein uniformly expressed on human plasma cells. Daratumumab has been utilized in recent years with unprecedented responses in multiple myeloma. In patients with relapsed or refractory AL amyloidosis, daratumumab has shown promising efficacy in terms of hematologic responses and improvement in organ function. Here, we report real-life treatment with Daratumumab in 33 AL amyloidosis patients treated within the Regional Tuscan Myeloma network at 5 centers with associated MGUS or SMM (n = 15) or symptomatic MM (n = 18). Patients were treated at relapsed/refractory disease stages (n = 29) with a median of one previous line of therapy or at diagnosis (n = 4). Daratumumab showed good efficacy, representing 60% of good hematological responses and 50% of organ responses in a real-life population of patients with an acceptable toxicity profile.

Ibrutinib is an oral inhibitor of Bruton tyrosine kinase approved for the treatment of chronic lymphocytic leukaemia, mantle cell lymphoma and refractory Waldenstrom's disease. It increases progression-free survival, overall survival, response rate. The most frequent adverse reactions, are increased risk in of bleeding and atrial fibrillation, but several reports of more dangerous rhythm disturbances have been recently reported in literature. A case of a patient with refractory Waldenstrom's disease, who developed ventricular fibrillation while taking ibrutinib, is reported, along with a concise literature review.

BACKGROUND: Intracranial involvement in multiple myeloma is extremely rare. The effect of new drugs (eg, thalidomide, bortezomib, lenalidomide) with respect to old drugs (eg, alkylators, steroids) has not been reported. METHODS: We collected clinical and biological data of patients presenting with an osteo-dural or primary dural multiple myeloma (OD-DMM) or a central nervous system myelomatosis (CNS-MM) by sending a questionnaire to the centers of the Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA). RESULTS: A total of 50 patients were registered. New therapies were used in 35 patients, whereas 15 patients received old treatments. Twenty-five out of 50 patients obtained a complete remission or a very good partial remission (CR+VGPR). Overall survival (OS) for CNS-MM was 6 months, for OD-DMM 25 months. OS was 25 months for patients treated with new agents versus 8 months with old agents. Improved OS and progression-free survival were predicted by response (CR+VGPR) and by patients who underwent stem cell transplantation versus chemotherapy. β2-Microglobulin >5 mmol/L was a poor prognostic factor. Multivariate analysis showed poor survival for patients with β2-microglobulin >5 mmol/L and better survival for patients achieving CR+VGPR. CONCLUSIONS: The overall data highlight the relevance of therapy with new drugs in intracranial myeloma, providing a framework for future clinical trials. Cancer 2011;. © 2011 American Cancer Society.

Thrombotic thrombocytopenic purpura (TTP), which is typically characterized by fever and central nervous system manifestations and hemolytic uremic syndrome (HUS), in which renal failure is a prominent feature are the most common thrombotic microangiopathies (TMAs). TTP is usually associated with a severe deficiency of ADAMTS13 [a metalloproteinase involved in the degradation of von Willebrand factor (vWF) multimers], causing excessive accumulation of ultra-large vWF multimers and platelet aggregation with organ failure. By contrast, patients with HUS or other TMAs usually display a normal or at least detectable ADAMTS13 activity. A TMA may be occasionally developed in association with HELLP (haemolysis, elevated liver enzymes, and low platelet count) syndrome, infections, cancer and bone marrow transplantation. In cancer patients, TMA may be related to chemotherapeutic regimens or the malignant disease itself. Occasionally, TMA is the first manifestation of an occult cancer, and in large series approximately 3% of patients who were originally diagnosed with TTP, were in fact harboring an occult malignancy. The pathogenesis of cancer-associated TMAs is not completely elucidated, but probably the most important factor is endothelial damage. However, cancer-associated TMAs show some distinct features that should promptly lead to complementary investigations for an underlying malignancy. Weakness, cough and dyspnoea, fever, weight loss, bone and abdominal pain are the most common presenting symptoms. Generally, biochemistry reveals markedly increased LDH levels, increased alkaline phosphatase and the blood smear shows erythromyelemia. Bone marrow biopsy is a valuable tool in order to establishing malignant seeding. Treatment of the underlying neoplasia is the mainstay of therapy and there is no role for plasmapheresis or plasma infusions.

Rituximab 375 mg/m(2) weekly for four weeks has significant activity in patients with immune thrombocytopenia. We evaluated the activity of lower dose rituximab (100 mg iv weekly for 4 weeks) in 28 adults with idiopathic thrombocytopenic purpura. Overall (platelet count > 50 x 10(9)/L) and complete responses (platelet count > 100 x 10(9)/L) were achieved in 21/28 (75%) and 12/28 (43%) patients respectively. The median time to response and time to complete response were 31 and 44 days respectively. After a median follow-up of 11 months (range 3-18), 7/21 (33%) patients relapsed and 3 needed further treatments. In patients with idiopathic thrombocytopenic purpura, lower dose rituximab seems to show similar activity to standard dose.

This randomized phase III clinical trial explored the efficacy of DaunoXome (DNX) versus Daunorubicin (DNR) in acute myeloid leukaemia (AML) patients aged >60 years. Three hundred and one AML patients were randomized to receive DNR (45 mg/m(2) days 1-3) or DNX (80 mg/m(2) days 1-3) plus cytarabine (AraC; 100 mg/m(2) days 1-7). Patients in complete remission (CR) received a course of the same drugs as consolidation and then were randomized for maintenance with AraC+ all trans retinoic acid or no further treatment. Among 153 patients in the DNR arm, 78 (51.0%) achieved CR, 55 (35.9%) were resistant and 20 (13.1%) died during induction. Among 148 patients in the DNX arm, 73 (49.3%) achieved CR, 47 (31.8%) were resistant and 28 (18.9%) died during induction. Univariate analysis showed no difference as to induction results. After CR, DNX showed a higher incidence of early deaths (12.5% vs. 2.6% at 6 months, P = 0.053) but a lower incidence of relapse beyond 6 months (59% vs. 78% at 24 months, P = 0.064), with a cross in overall survival (OS) and disease-free survival (DFS) curves and a later advantage for DNX arm after 12 months from diagnosis. DNX seems to improve OS and DFS in the long-term follow-up, because of a reduction in late relapses.

Intracranial multiple myeloma is uncommon. Cavernous sinus involvement has rarely been reported, generally associated with treatmentrefractory disease and poor outcome. We report clinical data and neuroradiologic findings of 3 patients with multiple myeloma and unilateral cavernous sinus involvement. At neuroradiology, this resulted from diffuse bone involvement as disease relapse (n = 2) or focal dural disease (n = 1) as the presenting sign. Interestingly, bortezomib treatment resulted in complete clinical resolution in 1 patient and partial clinical and significant magnetic resonance response in another, whereas in the literature, local radiation therapy has been reported as the only efficient treatment.

We evaluated safety and efficacy of imatinib (600 mg) in 36 c-KIT+ acute myeloid leukemia patients not amenable to receive conventional chemotherapy. No patient achieved complete remission. One patient obtained a hematologic improvement (platelet increase with transfusion independence). Median overall survival was 3 months (0.5-44+). Non-hematologic toxicity was overall mild.

In the past five years, the body of data concerning imatinib mesylate had certainly defined the role of this drug as very effective first line debulking therapy for CML patients. However, both the persistence of molecular disease in most of patients together with the evidence that discontinuation of imatinib inevitably exerts on a rapid loss of response, suggest that with imatinib alone the cure of CML is unlikely. CMLVAX100 is a peptide-based vaccine that specifically targets p210-b3a2 in CML cells through the induction of a peptide-specific T cell response in b3a2-CML vaccinated patients. We recently published the preliminary results of a pilot study testing the immunological response and antitumor activity of vaccinations with CMLVAX100 in 10 patients showing persistent residual disease during treatment with imatinib. We here report the results on a larger cohort of patients and with a longer follow up. Up to date 21 patients were enrolled in this study. After a median time of 24 months (range 12–50) of imatinib treatment, patients started vaccinations with CMLVAX100 showing different degrees of persistent residual disease: 8/21 patients presented with molecular disease, 10/21 showed residual cytogenetic disease (range 2–45% of Ph+ metaphases), while 3/21 presented only an hematological response (100% of Ph+ metaphases). No improvement of their residual disease was documented for a median of 12 months (range 6–24) before starting vaccinations. Vaccine treatment plan included 6 vaccinations at 2 weeks interval (immunization) and for responder patients additional boosts of vaccine every 4–6 months. So far 18/21 patients completed the immunization and are evaluable for response; in addition 8/18 received 4 further boosts of vaccine. After immunization, CMLVAX100 induced a prompt immunological response in most of the patients as 17/18 patients showed peptide specific T cell response in vitro and 12/18 developed a positive delayed type hypersensitivity response in vivo. After 6 vaccinations 6/10 patients with persisting cytogenetic disease reached a complete cytogenetic response (CCR), with 3 of them achieving an undetectable level of bcr-abl transcript. In addition, 3/5 evaluable patients starting vaccinations with persistent molecular disease, further reduced their bcr-abl level, wth one reaching molecular negativity. None of the 3 patients vaccinated in hematological remission had cytogenetic response. Of the 8 patients who underwent 4 additional boosts of vaccine, one reached a complete molecular response, 5 maintained the response obtained after immunization, while 2 patients who previously achieved an undetectable level of bcr-abl transcript, lost the complete molecular response, while maintaining CCR, thus suggesting that a 6 months interval between boosts could be too long to maintain an efficient immune control on residual leukemic cells. In conclusion, we confirm that CMLVAX100 has a synergistic antitumor effect with imatinib in CML patients with persistent minimal residual disease. However, follow-up data recommend that closer boosts of vaccine are necessary in order to maintain an optimal level of response.

e20021 Background: Metastatic melanoma (MM) is a disease with poor prognosis; Vemurafenib (V) is a potent inhibitor of BRAF with V600E mutation with well established antitumor activity in this sett...

Thalidomide represents a recent and innovative therapeutic approach in multiple myeloma. Main toxicity usually consists in somnolence, constipation, peripheral neuropathy and deep vein thrombosis, but, unlike alkylating agents, thalidomide is reported to rarely induce severe hematologic toxicity. The majority of patients developing neutropenia are heavily pretreated with three or more lines of chemotherapy. Here, we report, for the first time, clinical and laboratory data of a 66-year-old female patient with multiple myeloma at diagnosis who, after 4 weeks of thalidomide treatment, developed a grade 4 WHO neutropenia with septicemia. A brief review of the literature and suggestions for possible predictive factors of this toxicity are made.

Whereas hyperdiploidy is a frequent cytogenetic abnormality in acute lymphoblastic leukemia, tetraploidy is rarely observed in acute myeloblastic leukemia (AML), in which gains and losses of whole chromosomes do occur frequently [1–4]. A 76-year-old man was admitted to our division with dyspnea and weakness. Peripheral blood cell analysis showed white blood cell count 29.6 × 10/mL with 90% blast cells, hemoglobin 9.4 g/dL, and platelets 55 × 10/mL. Physical examination findings were normal, except for liver enlargement. Bone marrow examination confirmed a diagnosis of AML M5a with 90% blast cells. Leukemic cells

Abstract 1371 Background: IGHV1-69 gene identifies the most frequent IGHV gene in chronic lymphocytic leukemia (CLL) and identifies the paradigm of unmutated CLL (U-CLL), being used in roughly 1/3 U-CLL. It is often rearranged to form subsets of stereotyped HCDR3 patterns, likely selected and transformed from the natural naïve B-cell repertoire (Blood. 2010; 115:71-7). Being unmutated, IGHV1-69 CLL are hypothetically expected to have competent tumor B-cell receptors (BCR) and to progress more rapidly. However, it has not been investigated if progression occurs similarly in all the subsets. Aims: we aimed to investigate the prognostic significance of mutational status and of stereotypic B-cell receptors in IGHV1-69+ CLL. Methods: Nucleotide sequences of the tumor IGHV1-69/D/J rearrangement, clinical and molecular prognostic parameters at diagnosis and clinical status at follow-up of 294 IGHV1-69+ CLL patients were obtained from 22 hematological Institutions in Italy. CLL B-cell derived IGHV1-69 rearrangements were scanned for HCDR3 stereotypic patterns and assigned to subsets according to the criteria by Murray et al (Blood. 2008; 111: 1524–1533). Enpoint of outcome was time to progression requiring first treatment according to NCI criteria (TTFT) in Rai stage 0 CLL. Results: Of 294 IGHV1-69+ CLL, 264 (89,8%) were unmutated, 168 (57,1%) were assigned to subsets, of which subsets 7 (n=23, 7,8%), 6 (17, 5,8%), 3 (13, 4,4%), 5 (10, 3,4%) and 9 (10, 3,4%) were the most frequent. CD38, ZAP70, normal or sole del13, +12, del11 and del17p scored positive in 109/264 (58,7%), 139/245 (56,7%), 128/248 (50,5%), 51/248 (20,6%), 43/248 (17,3%) and 34/248 (13,7%). CLLs were reclassified as 18 (6,1%) clinical MBL, 101 (34,4%) Rai 0, 155 (52,7%) Rai I-II and 20 (6,8%) Rai III-IV CLL. Subset 6 was also UM in 16/17 (94,1%) cases. Prevalence of CD38 (p Conclusions: our analysis documents and confirms that unmutated status of IGHV, and not stereotypy, is a relevant prognosticator of outcome (TTFT) in CLL. In the IGHV1-69 CLL it exclude a role of IGHV gene use for CLL progression. However, the good prognosis of Rai 0 U-CLL assigned to subset 6 suggests a differential clinical benign course of this particular subset, irrelevant of unmutated status. One possibility is that the IGHV1-69/D3-16/J3 rearrangements of subset 6 produce a tumor-specific BCR with stereotypic HCDR3 patterns that are anergized by antigen while circulating in the peripheral blood in early stage (Rai 0) CLL. Disclosures: No relevant conflicts of interest to declare.

The prognosis of acute myeloid leukemia (AML) in older adults is generally poor. Standard cytotoxic chemotherapy is scarcely tolerated and usually followed by low complete remission (CR) rate and short remission duration. Gemtuzumab ozogamicin (GO), is an anti-CD33 antibody conjugated to calicheamicin, that has shown activity as single agent in relapsed AML with a favorable safety profile. Few data have so far reported on GO associated with conventional chemotherapy in the elderly and less is known on the role of this antibody-targeted therapy as single consolidation treatment in this patients population. We here report a pilot experience on the feasibility and outcome of an age-adjusted combination regimen with GO, fludarabine (FLUDA), arabinisyl-cytosine (AC) and idarubicine (IDA) (GO-FLAI regimen) followed by two courses of GO alone as consolidation treatment in a group of elderly AML patients. We treated with GO-FLAI regimen 12 patients: 5 with primary leukemia, 5 with a prior history of myelodisplasia and 2 with relapsed disease. They received FLUDA 25 mg/m2, AC 1 g/m2 and IDA 5 mg/m2 for 3 days; on the fourth day GO was administered at 3 mg/m2. Two cycles were planned. After induction therapy, patients achieving a response received two courses with GO at 3 or 6 mg/m2. The median age was 71.5 years (range 65–80), the male/female rate was 6/6. Eigth patients had normal kariotype, 4 had one ore more cytogenetic abnormalities. After induction regimen 9/12 patients reached a CR (75%), 1/12 (8%) patient obtained a partial remission (PR), and 2/12 (16%) patients were resistant to the treatment. The most common adverse events at this stage of treatment were fever and chills during the administration of GO, infections secondary to neutropenia (66%) and transient grade I/II gastrointestinal toxicity. No hepatic veno-occlusive disease nor grade III/IV bleeding were recordered. The median time to recovery from severe neutropenia (ANC < 0.5 x 109/L) was 16 days and from severe thrombocytopenia (platelets < 20 x 109/L) was 14 days. No patient died of GO-FLAI related mortality. As consolidation treatment, all responders patients (9 CR plus 1 PR) underwent two additional GO administration at 3mg/m2 (6/10 patients) or 6mg/m2 (4/10 patients). All 10 patients maintained their response after the two courses of GO for a median of 5.5 months (range 1-15) with 4/10 patients relapsing after 5, 7, 7 and 9 months respectively. Median overall survival was 10 months (range 1-23) from diagnosis. All GO administrations were performed in an out-patient setting, treatment was generally well tolerated and myelosuppression was moderate both at the 3 and 6 mg/m2 dose schedule. Nevertheless it has to be noted, that two patients (1 CR, 1 PR) died because of a CNS hemorrhage despite a number of platelets ≥ 20 x 109/L (one patient after receiving 1 course of GO at 3mg/m2 and one patient after receiving 2 courses at 6 mg/m2, respectively).We conclude that GO-FLAI regimen followed by two GO administrations is a feasible, fairly effective and well tolerated treatment for AML elderly patients. In particular the CR rate appears consistent with previous studies employing conventional chemotherapy only. Further studies are required to assert, after a longer follow-up, if this induction and consolidation target-based regimen can improve DFS, which is the major problem of elderly AML patients.

Although the success of imatinib mesylate therapy represents an exciting advance in targeted cancer therapy, it has still to be determined whether responses to this p210 inhibitor in chronic myeloid leukemia (CML) patients will be durable. In fact most of clinical studies agree on the evidence of a persistent molecular disease in the majority of treated patients and altough the absolute level of bcr-abl transcript may vary over the treatment, yet a molecular complete response is of rare observation. In addition, discontinuation of imatinib exerts always in rapid loss of response. In accordance to this the persistence of malignant progenitors in patients in complete cytogenetic response (CCR) after short term imatinib treatment, has been recently demonstrated. In particular, Bathia et al. showed in 12/15 patients studied after a median time of 10 months of imatinib treatment a median of 11% of residual CML CD34+ progenitors in the bone marrow (by FISH Dual Fusion bcr/abl analysis)while only 3/15 patients had no detectable residual CD34+ cells. Less is known about residual Ph+/CD34+ cells surviving after a prolonged therapy with this targeting drug. Thus, we evaluated the amount of bone marrow residual CD34+ cells in 17 CML patients in stable CCR after a long lasting treatment with imatinib. At the time of evaluation, the patients were on conventional dose (400mg) Imatinib for a median time of 48 months (range 36–58 months) having achieved a CCR status (conventionally defined as the complete absence of t(9;22) on caryotypic analysis) within 3 to 6 months of treatment. However all of them still showed molecular disease as detected by nested RT-PCR. Bone marrow CD34+ cell-enriched populations were selected from mononuclear cells using immunomagnetic column separation and were evaluated after cytospin by FISH using a bcr-abl Dual Color Extra Signal Probe(LSI bcr-abl ES, Vysis), that is able to detect bcr-abl fusion in interphase nuclei with a false positive signal rate close to 0. A minimum of 100 CD34+ nuclei per each sample were evaluated. Interestingly, in 8/17 patients no Ph+/CD34+ cells were detected, while in the remaining 9/17 patients a median of 2% (range 0.5–11%) of bcr-abl positive progenitors were still observed. In this small selected serie of patients prolonged treatment with imatinib appears to be correlated with a lower, yet detectable, amount of residual bone marrow Ph+/CD34+ cells when compared to previously published data. This result could be partly explained with the different specificity and sensitivity of the probe used (bcr/abl ES

(2005). Massive intravascular hemolysis: a fatal complication of Clostridium perfringens septicemia in a patient with acute lymphoblastic leukemia. Leukemia & Lymphoma: Vol. 46, No. 5, pp. 793-793.