Acute Myeloid Leukemia with NPM1 Mutation and Disseminated Leukemia Cutis: Achievement of Molecular Complete Remission by Venetoclax/Azacitidine Combination in a Very Old Patient.

We describe a case of acute myeloid leukemia with NPM1 mutation and disseminated leukemia cutis in a very old patient, who achieved a long-lasting response to the azacitidine/venetoclax combination with molecular complete remission, given the potential value of this rarely observed clinical outcome.

Acute hepatitis-like presentation with cholestasis of CBFB-MYH11-positive acute myeloid leukemia in an adult male: a case report.

BACKGROUND: Liver involvement in adults with acute myeloid leukemia is uncommon. Most of the case reports describe acute liver failure or obstructive jaundice, while acute hepatitis is rarely mentioned. We report a patient with acute myeloid leukemia who presented with clinical, biochemical, and radiological signs of acute hepatitis that totally regressed after chemotherapy. CASE PRESENTATION: A 38-year-old Caucasian man presented with fever, cough, and mild fatigue. Laboratory workup showed anemia, thrombocytopenia, severe leukocytosis, transaminitis, and hyperbilirubinemia. Imaging of the abdomen (ultrasound and magnetic resonance) showed hepatomegaly, splenomegaly, upper limits portal veins diameters, increased thickness of the gallbladder wall, and significant abdominal lymph nodes. Peripheral blood smear and bone marrow evaluation were consistent with acute myeloid leukemia, and liver biopsy showed massive sinusoidal and portal infiltration by leukemic cells. After remission-inducing chemotherapy, there was complete normalization of liver function tests, and liver, spleen, and portal vein size. CONCLUSIONS: This case highlights the importance of taking acute myeloid leukemia into account as a possible cause of liver damage to make a rapid diagnosis and start appropriate treatment that may lead to hematological remission and hepatic dysfunction resolution.

CPX-351: An Old Scheme with a New Formulation in the Treatment of High-Risk AML.

Therapy-related acute myeloid leukemia (t-AML) and acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) represent aggressive diseases characterized by a dismal prognosis if compared with de novo acute myeloid leukemia, especially in older patients. In these AML subsets, standard chemotherapy regimens produce poor response rates and unsatisfactory outcomes. Historically, conventional approaches consisted of an anthracycline combined with continuous infusion of cytarabine for 7 days, the "3+7" regimen. Several attempts have been conducted to ameliorate this combination regimen but inconsistent improvements in response rates and no significant changes in overall survival have been observed, until the recent introduction of targeted molecules. A liposomal formulation of traditional chemotherapy agents cytarabine and daunorubicin, termed CPX-351, enhances pharmacodynamics and synergistic effects through the maintenance of the optimal 5:1 molar ratio, which extends the treatment's half-life and increases the bone marrow tropism of the drug. The use of CPX-351 in newly diagnosed AML-MRC and t-AML patients aged 60-75 years has demonstrated superior remission rates compared to conventional chemotherapy and improvements in event-free and overall survival. Recently, published data from a 5-year follow-up highlighted evidence that CPX-351 has the ability to produce and contribute to long-term remission and survival in older patients with newly diagnosed high-risk/secondary AML. Future perspectives include evaluation of dose intensification with CPX-351 in high-risk settings, combining this agent with targeted therapies, and better understanding the mechanism of improved responses in t-AML and AML-MRC. In this review, we will examine the role of CPX-351 inside the new AML therapeutic scenario and how its employment could potentially modify the treatment algorithm of high-risk and elderly patients with AML.

Reduced transmission of Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-KP) in patients with haematological malignancies hospitalized in an Italian hospital during the COVID-19 pandemic.

OBJECTIVES: During the lockdown that started in Italy on 10 March 2020 to address the COVID-19 pandemic, aggressive procedures were implemented to prevent SARS-CoV-2 transmission in SARS-CoV-2-negative patients with haematological malignancies. These efforts progressively reduced Klebsiella pneumonia carbapenemase-producing K. pneumoniae (KPC-KP) spread among these patients. Here we evaluated the potential effects of measures against COVID-19 that reduced KPC-KP transmission. PATIENTS AND METHODS: We analysed KPC-KP spread among 123 patients with haematological malignancies, hospitalized between March and August 2020, who were managed using measures against COVID-19. Their outcomes were compared with those of 80 patients hospitalized during the preceding 4 months (November 2019-February 2020). RESULTS: During March-August 2020, 15.5% of hospitalized patients were KPC-KP positive, compared with 52.5% in November 2019-February 2020 (P < 0.0001); 8% and 27.5% of patients in these two groups were newly KPC-KP positive, respectively (P = 0.0003). There were eight new KPC-KP-positive patients during January 2020 and none during June 2020. The weekly rate of hospitalized KPC-KP-positive patients decreased from 50% during March 2020 to 17% during August 2020. Four KPC-KP bloodstream infections (BSIs) were experienced by 123 patients (3%) in March-August 2020, and seven BSIs (one fatal) by 80 patients (8%) in November 2019-February 2020 (P = 0.02). Consumption and expense of ceftazidime/avibactam administered to KPC-KP-positive patients significantly decreased in March-August 2020. CONCLUSIONS: Aggressive strategies to prevent SARS-CoV-2 transmission were applied to all hospitalized patients, characterized by high levels of KPC-KP endemicity and nosocomial transmission. Such measures prevented SARS-CoV-2 infection acquisition and KPC-KP horizontal transmission. Reduced KPC-KP spread, fewer associated clinical complications and decreased ceftazidime/avibactam consumption represented unexpected 'collateral benefits' of strategies to prevent COVID-19.

Emerging tyrosine kinase inhibitors for the treatment of adult acute lymphoblastic leukemia.

Introduction: The broadening of targeted and immunotherapeutic strategies markedly impacted on the management of acute lymphoblastic leukemia (ALL). The advent of tyrosine kinase inhibitors (TKIs) changed the history of Philadelphia-chromosome positive (Ph+) ALL. Nowadays, almost all Ph+ ALL patients treated with TKIs achieve a complete hematologic response, and most become minimal residual disease negative. In Ph- ALL, genomic profiling studies have identified a subtype associated with a high relapse risk and a transcriptional profile similar to that of Ph+ ALL, the so-called Ph-like ALL. Given the high prevalence of kinase-activating lesions in this subset, there is compelling evidence from experimental models and clinical observations favoring TKI administration.Areas covered: We discuss the main findings exploring the efficacy of TKIs in ALL.Expert opinion: The use of more potent TKIs will further enhance the inhibitory activity on leukemia cells and increase the possibility of eradicating the disease at a molecular level. In the future, 'combined' approaches of different inhibitors may be considered to prevent/avoid resistance and/or mutations. A rapid identification of Ph-like ALL patients is needed to propose early TKI-based intervention. Several questions remain open, including the initial TKI choice in Ph+ ALL and whether Ph-like ALL patients might benefit from immunotherapy.

CD33 Expression and Gentuzumab Ozogamicin in Acute Myeloid Leukemia: Two Sides of the Same Coin.

Acute myeloid leukemia (AML), the most frequent acute leukemia in adults, has been historically treated with infusional cytarabine (ara-c) + daunorubicin (3 + 7) for at least 40 years. The first "target therapy" to be introduced was the monoclonal anti-CD33 gemtuzumab ozogamicin (GO) in 2004. Unfortunately, in 2010 it was voluntarily withdrawn from the market both for safety reasons related to potential liver toxicity and veno-occlusive disease (VOD) and because clinical studies failed to confirm the clinical benefit during induction and maintenance. Seven years later, GO was re-approved based on new data, including insights into its mechanism of action on its target receptor CD33 expressed on myeloid cells. The present review focuses on current biological information and clinical data from several studies investigating GO. Cytogenetic, molecular, and immunophenotypic data are now able to predict the potential positive advantages of GO, with the exception of high-risk AML patients who do not seem to benefit. GO can be considered a 'repurposed drug' that could be beneficial for some patients with AML, mostly in combination with new drugs already approved or currently in testing.

Erythropoietin treatment in chronic phase chronic myeloid leukemia patients treated with frontline imatinib who developed late anemia.

BACKGROUND: Role of erythropoietin (EPO) in the treatment of late anemia in patients with Chronic Myeloid Leukemia (CML) is still undefined. METHODS: Fifty CML patients treated at 14 institutions with frontline imatinib for at least 12 months and in stable complete cytogenetic response who developed a late chronic anemia treated with EPO were retrospectively evaluated. RESULTS: Median time from imatinib start to EPO treatment was 42.2 months [interquartile range (IQR) 20.8-91.9]. Median Hb value at EPO starting time was 9.9 g/dL (IQR 8.9-10.3): Eleven patients (22.0%) were transfusion dependent. Alpha-EPO (40 000 UI weekly) was employed in 37 patients, beta-EPO (30 000 UI weekly) in 9 patients, zeta-EPO (40 000 UI weekly) in 2 patients, and darbepoetin (150 mcg/weekly) in the remaining 2 patients. On the whole, 41 patients (82.0%) achieved an erythroid response, defined as a stable (>3 months) improvement >1.5 g/dL of Hb level, and 9 patients (18.0%) indeed resulted resistant. Among responding patients, 10 relapsed after a median time from EPO start of 20.7 months (IQR 10.8-63.7). No EPO-related toxicity was observed. CONCLUSIONS: Results of EPO treatment for late chronic anemia during long-lasting imatinib therapy are encouraging, with a high rate of response.

Pulmonary infections in patients with myelodysplastic syndromes receiving frontline azacytidine treatment.

Pulmonary infections (PIs) are a major complication of patients with myelodysplastic syndromes (MDS). We retrospectively evaluated 234 MDS patients treated with azacytidine (AZA). The total number of AZA cycles was 2886 (median 8 cycles per patient). There were 111 episodes of PI (3.8% of AZA cycles) in 81 patients (34.6%). PIs were considered of fungal origin in 27 cases (24.3%), associated to bacteremia in 11 cases (9.9%), to influenza infection in two cases (1.8%) and of unknown origin in the remaining 71 cases (64.0%). Forty-five PI episodes were documented in cycles 1 to 4 of AZA (5.1% of 875 cycles) and the remaining 66 episodes beyond the fourth cycle (3.2% of 2011 cycles) (P = .017). Overall, a fungal PI was documented in 13/875 (1.5%) cycles 1 to 4 and in 13/2011 (0.6%) cycles beyond the fourth cycle (P = .001). A baseline chronic pulmonary disease was significantly associated to a higher risk of severe PIs. In the survival analysis, cases of PI in patients who progressed to acute leukemia (PAL) were excluded, in view of the predominant influence of PAL on the outcome of the patients. A PI unrelated to PAL documented during the first 4 AZA cycles was an independent factor predicting lower survival (OR, 2.13; 95% CI, 1.37-3.33; P = .001). In conclusion, PIs are common in MDS patients receiving AZA, in particular during the first cycles of treatment and are associated with an unfavorable outcome. The results of our study raise the issue of the need of a tailored infection prevention strategy.

Ibrutinib-based therapy impaired neutrophils microbicidal activity in patients with chronic lymphocytic leukemia during the early phases of treatment.

Ibrutinib is a tyrosine kinase inhibitor used in the treatment of a variety of lymphoid malignancies, including chronic lymphocytic leukemia (CLL). Drugs inhibiting B-cell-receptor (BCR)-associated kinases, including BTK inhibitors, act on B cells and on a wide spectrum of tissues and cells, including innate immunity cells. Thus, alterations in the Bruton's tyrosine kinase (BTK) kinase function could lead to an impairment of innate immune cells functions and to an increased infectious risk in patients receiving BTK inhibitors. We analyzed in vivo neutrophils oxidative burst, neutrophils granules release and cytokine production in relapsed/refractory CLL patients treated over time with ibrutinib as single-agent. We observed a dramatic reduction of neutrophils oxidative burst, Fc gamma receptors (FcγRs)-mediated degranulation and IL-8 plasma levels already after the first forty-eight hours of therapy with ibrutinib. However, ibrutinib treatment did not alter the surface expression of CD11b nor cytokine and proteinases release not mediated by FcγRs engagement. After three weeks, oxidative burst was still impaired, while degranulation and IL-8 levels were restored. In a group of CLL patients who survived for more than three years, all processes triggered by FcγRs completely recovered except the release of neutrophil elastase (NE) and IL-8. In conclusion, during the initial phases of ibrutinib therapy, the reduction of IL-8, NE, myeloperoxidase (MPO) levels and oxidative burst negatively impacted on mechanisms involved in neutrophils microbicidal activity.

Incidence of Clinically Significant (≤10 g/dL) Late Anemia in Elderly Patients with Newly Diagnosed Chronic Myeloid Leukemia Treated with Imatinib.

BACKGROUND: In elderly patients with chronic myeloid leukemia (CML) responsive to imatinib, the incidence of clinically significant (CS) late chronic anemia is still unknown. MATERIALS AND METHODS: To highlight this issue, we revised retrospectively 81 CML patients aged >60 years treated at our Institution with front-line imatinib for at least 24 months in durable complete cytogenetic response (CCyR). CS late chronic anemia was defined as the presence of persistent (>6 months) and otherwise unexplained Hb levels ≤10 g/dL, which occurred >6 months from imatinib start. RESULTS: A condition of CS late chronic anemia occurred in 22 out of 81 patients (27.2%) at different intervals from imatinib start. Seven out of 22 patients (31.8%) needed packed red cell transfusions during the follow-up. At diagnosis, patients who developed CS late chronic anemia were significantly older and had a lower Hb median level. Six out of 22 patients with CS late chronic anemia received subcutaneous recombinant alpha-erythropoietin (EPO) at the standard dosage of 40,000 IU weekly: all 6 patients achieved an erythroid response. A significantly worse event-free survival (EFS) in patients with untreated CS late chronic anemia was observed (p = 0.012). CONCLUSIONS: CS late chronic anemia during long-term treatment with imatinib is a common complication in responsive elderly patients, with worse EFS if untreated. Results with EPO are encouraging, but larger studies are warranted to define its role.

Is re-challenge still an option as salvage therapy in multiple myeloma? The case of REal-life BOrtezomib re-Use as secoND treatment for relapsed patients exposed frontline to bortezomib-based therapies (the REBOUND Study).

Therapeutic re-challenge is currently a debated issue in the field of multiple myeloma (MM), given the recent availability of several new drugs and combinations. However, very few specific evidences are available about bortezomib re-use at first relapse. This multicenter, observational, retrospective study enrolled 134 MM patients with significant response after bortezomib-based frontline regimens and who had received a first salvage treatment containing bortezomib at relapse. The overall response rate was 71%, including 40% partial responses, 24% very good partial responses, and 7% complete responses. Re-treatment was well-tolerated, with no significant new or unexpected toxicities observed. The median duration of second progression-free survival (PFS) was 15 months, while median PFS2 was 55 months. With a median follow-up of 56 months, overall survival was 94 months for the entire series, without significant differences between patients undergoing or not undergoing transplant procedures. This real-life survey indicates that re-treatment including bortezomib as a first salvage therapy could be still considered in MM patients achieving durable response after initial exposure to bortezomib.

Clinical results according to age in patients with chronic myeloid leukemia receiving imatinib frontline: The younger, the later, the worse?

OBJECTIVES: To evaluate differences in clinical results according to age among patients with chronic myeloid leukemia (CML). METHODS: 207 consecutive CML patients treated with imatinib frontline were revised, dividing them in young adults (>20 < 45 years) (YA), middle-aged adults (≥45 < 65 years) (MA) and elderly (≥65 years) (EL). RESULTS: Cumulative incidence of complete cytogenetic response (CCyR) and major molecular response (MMolR) were significantly higher in MA compared with YA and EL (P < .001 for CCyR and P = .001 for MMolR). Number of total events was lower in MA (8 [11.1%] vs 21 [34.4%] in YA and 28 [37.8%] in EL, P = .001): no difference was observed for blastic evolution (P = .478). Number of deaths was higher in the EL (12 [16.2%] vs 2 [3.2%] in YA and 0 in MA, P < .001): however, 11/12 deaths in EL were not related to CML. The PFS curve in MA was significantly longer than in YA and in EL (P = .02). The OS curve in EL was significantly shorter than in YA and in MA (P < .001). CONCLUSIONS: Age at diagnosis influences significantly the course of CML patients treated with imatinib: a possible explanation of the counterintuitive worse course in YA is the delayed diagnosis compared to elderly.

Cyclophosphamide's addition in relapsed/refractory multiple myeloma patients with biochemical progression during lenalidomide-dexamethasone treatment.

OBJECTIVE: The aim of this study was to evaluate the addition of cyclophosphamide in relapsed-refractory multiple myeloma patients (RRMM) who experienced biochemical relapse or progression without CRAB, during treatment with lenalidomide and dexamethasone (Rd), to slow down the progression in active relapse. METHODS: This analysis included 31 patients with RRMM treated with Rd who received cyclophosphamide (CRd) at biochemical relapse. The CRd regimen was continued until disease progression. RESULTS: The median number of CRd cycles administered was 8 (range: 1-35). A response was observed in 9 (29%) patients. After a median observation time of 11 months, the median overall survival (OS) from the beginning of CRd was 17.7 months. The median progression-free survival (PFS) from the beginning of CRd was 13.1 months. CONCLUSION: The addition of cyclophosphamide delays the progression in patients who present a biochemical relapse during Rd treatment. The response rate and the duration of PFS obtained with minimal toxicities and low costs induced us to setting up a randomized clinical trial.

Managing treatment-related peripheral neuropathy in patients with multiple myeloma.

Peripheral neuropathy is one of the most important complications of multiple myeloma treatment. Neurological damage can be observed at the onset of the disease, due to the effect of monoclonal protein or radicular compression, but more often is treatment related. Vinca alkaloids in the past era, and more recently, thalidomide and bortezomib are mainly responsible. Degeneration of dorsal root ganglion is common, prevalently related to angiogenesis inhibition and cytokine modulation in the case of thalidomide and inhibition of the ubiquitin proteasome system in the case of bortezomib. Sensory neuropathy and neuropathic pain are more common; motor neuropathy and autonomic damage are less frequently observed. Neurotoxicity often affects patient's quality of life and requires dose modification or withdrawal of therapy, with a possible effect on the overall response. A prompt recognition of predisposing factors (such as diabetes mellitus, alcohol abuse, vitamin deficiencies, or viral infections) and appearance of signs and symptoms, through a periodic neurological assessment with appropriate scales, is extremely important. Effective management of treatment at the emergence of peripheral neuropathy can minimize the incidence and severity of this complication and preserve therapeutic efficacy. Dose adjustment could be necessary during treatment; moreover, gabapentin or pregabalin, tricyclic antidepressants, serotonin and norepinephrine reuptake inhibitors, carbamazepine, and opioid-type analgesics are suggested according to the pain severity. Some authors reported that patients who develop peripheral neuropathy during their multiple myeloma treatments presented a particular gene expression profile; therefore, future studies could be helpful for a better understanding of possible biological pathways underlying neurotoxicity.