Francesca G. Rossi

Second malignancies in essential thrombocythemia (ET): a retrospective analysis of 331 patients with long-term follow-up from a single institution

Abstract Essential thrombocythemia (ET) is a myeloproliferative disorder characterized by an indolent clinical course, with a median survival exceeding 20 years. A minority of patients undergo thrombohemorrhagic complications, which might be prevented by cytoreductive treatment in high risk categories. Alkylating agents (ALK) have been demonstrated to increase the risk of acute leukemia and myelodysplastic syndromes in patients with myeloproliferative disorders, whereas the potential oncogenicity of hydroxyurea (HU) remains a matter of debate. In this study, we retrospectively investigated long-term development of hematological and non-hematological second malignancies in 331 patients with ET, analyzing possible associations with chemotherapy treatments. Median follow-up was 108 months. Of the 194 patients who were treated with chemotherapy, 116 (60%) received only HU, 38 (19·5%) only ALK (busulfan or melphalan) and 40 (20·5%) ALK followed by HU. After a median time of 87 months from the diagnosis of ET, 43 patients developed a second malignancy, hematological in 15 and non-hematological in 28, for an overall cumulative incidence of 13%. According to the type of treatment, second malignancies were documented in 11·2% of patients treated with only HU, in 26·3% of patients who received only ALK, and in 25% of those treated with ALK followed by HU. Ten cases (7·3%) were recorded among the 137 patients who did not receive any treatment. Our analysis revealed a significant association between treatment with alkylating agents and an increased risk of developing second hematological malignancies, whereas no such association was detected with regard to treatment with hydroxyurea single agent in our ET population. In addition, different treatment strategies did not affect the risk of developing second solid cancers.

Impact of febrile neutropenia on R-CHOP chemotherapy delivery and hospitalizations among patients with diffuse large B-cell lymphoma

PurposeThis analysis from an observational study of clinical practice describes the impact of febrile neutropenia (FN) on chemotherapy delivery and hospitalizations.MethodsAdults with diffuse large B-cell lymphoma (DLBCL) scheduled to receive ≥3 cycles of 2- or 3-weekly CHOP with rituximab (R-CHOP-14/21) were eligible. Primary outcome was incidence of FN.ResultsFN data were available for 409 patients receiving R-CHOP-14 and 702 patients receiving R-CHOP-21. FN incidence was R-CHOP-14, 20% (81/409) and R-CHOP-21, 19% (133/702). Rates of primary prophylaxis with granulocyte-colony stimulating factor were R-CHOP-14, 84% (345/409) and R-CHOP-21, 36% (252/702). A large number of patients experienced their first FN episode in cycle 1 (R-CHOP-14, 24/81 [30%]; R-CHOP-21, 63/133 [47%]). Multiple risk factors (≥2) for FN were more frequent in patients experiencing FN than in patients not experiencing FN (R-CHOP-14, 60/81 [74%] versus 179/328 [55%]; R-CHOP-21, 98/133 [74%] versus 339/569 [60%]). A similar trend was observed for unplanned hospitalizations (R-CHOP-14, 63/81 [78%] versus 68/328 [21%]; R-CHOP-21, 105/133 [79%] versus 100/569 [18%]). Achievement of chemotherapy relative dose intensity ≥90% was lower among patients experiencing FN than in patients not experiencing FN (R-CHOP-14, 30/81 [37%] versus 234/328 [71%]; R-CHOP-21, 83/133 [62%] versus 434/569 [76%]).ConclusionsIn patients with DLBCL treated with R-CHOP-14 or R-CHOP-21, patients with an event of FN were more likely to experience suboptimal chemotherapy delivery and increased incidence of unplanned hospitalizations than those without FN. FN-related hospitalizations are likely to impact chemotherapy delivery and to incur substantial costs.

The need for improved neutropenia risk assessment in DLBCL patients receiving R-CHOP-21: Findings from clinical practice

Febrile neutropenia (FN) risk-assessment and granulocyte-colony stimulating factor (G-CSF) prophylaxis use in clinical practice was evaluated in patients with diffuse large B-cell lymphoma receiving R-CHOP-21. More G-CSF primary prophylaxis was used in patients assessed as high FN risk, but R-CHOP-21 was associated with substantial myelotoxicity in both high- and low-risk groups. In a multivariate analysis, older age, poor performance status, lower baseline hemoglobin, and lack of G-CSF prophylaxis were significantly associated with occurrence of FN in any cycle. Results highlight the need for improved FN risk-assessment and thorough guideline adherence to further reduce FN and better support chemotherapy delivery.

Impact of Age Group on Febrile Neutropenia Risk Assessment and Management in Patients With Diffuse Large B-Cell Lymphoma Treated With R-CHOP Regimens

UNLABELLED Improving the management of elderly patients with lymphoma is of increasing relevance. One thousand one hundred thirteen patients with diffuse large B-cell lymphoma (DLBCL) received rituximab (R)-CHOP (cyclophosphamide, doxorubicin [hydroxydaunorubicin], vincristine [Oncovin], and prednisone) in an observational study. Both older and younger patients failed to receive growth factor support in accordance with international guidelines; patients 65 years and older were more susceptible to febrile neutropenia (FN) and its consequences. Better application of guidelines could reduce rates of FN and improve outcomes. BACKGROUND The incidence of diffuse large B-cell lymphoma (DLBCL) is increasing in the elderly population, which is a more challenging population to treat because of comorbidities and enhanced sensitivity to chemotherapy toxicities. This analysis evaluated the impact of age group on assessment of febrile neutropenia (FN) risk, supportive care management, and chemotherapy delivery. METHODS The IMPACT non-Hodgkin lymphoma (NHL) trial was an observational study conducted in Europe and Australia. This analysis included 1113 patients with DLBCL treated with rituximab (R)-CHOP (cyclophosphamide, doxorubicin [hydroxydaunorubicin], vincristine [Oncovin], and prednisone) every 14 days (n = 409) or every 21 days (n = 704). Outcomes were reported for ages < 65 years and ≥ 65 years. The primary outcome in this analysis was the proportion of patients assessed by investigators as having an overall high (≥ 20%) FN risk who received granulocyte colony-stimulating factor (G-CSF) primary prophylaxis. RESULTS For R-CHOP-14, investigators assessed 78% of younger patients and 80% of older patients with ≥ 20% risk of FN, although 14% of younger and 19% of older high-risk patients did not receive G-CSF primary prophylaxis. For R-CHOP-21, investigators assessed 52% of younger and 71% of older patients with ≥ 20% risk of FN; however, 61% of younger and 47% of older high-risk patients did not receive G-CSF primary prophylaxis. Regardless of chemotherapy regimen, rates of FN and unplanned hospitalization were higher in older patients, and delivery of chemotherapy was poorer. CONCLUSION Adherence to G-CSF guidelines in patients assessed with high FN risk was suboptimal in patients with DLBCL receiving R-CHOP chemotherapy, with substantial proportions of both younger and older patients receiving R-CHOP-21 failing to receive optimal G-CSF support. Better application of guidelines could reduce FN rates and improve outcomes.

Anemia and erythropoiesis-stimulating agent administration in patients with non-Hodgkin lymphoma treated with cyclophosphamide, doxorubicin, vincristine, and prednisolone ± rituximab chemotherapy: results from an observational study.

CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) ± rituximab [(±R)CHOP] is the current standard of care for aggressive non-Hodgkin lymphoma (NHL). Anemia resulting from chemotherapy can be treated with erythropoiesis-stimulating agents (ESAs). As part of the observational IMPACT NHL study, data were collected on ESA use and anemia-related outcomes in 1829 adults receiving (±R)CHOP-14 or (±R)CHOP-21. Overall, 33% of patients were anemic during chemotherapy. Older age, lower baseline hemoglobin (Hb), worse performance status, more advanced disease stage, and use of CHOP-14 were significant predictors of transfusion and anemia in logistic regression models. ESAs were received by 404 patients, usually in response to low or declining Hb levels. Most patients (65%) had Hb 9–11 g/dL at ESA initiation, and 89% (Kaplan–Meier percentage) achieved Hb 10–12 g/dL. In conclusion, two-thirds of anemic patients with NHL receiving (±R)CHOP initiated ESA treatment at Hb 9–11 g/dL, and most achieved target Hb levels (10–12 g/dL).

Proposal and Validation of Prognostic Scoring Systems for IgG and IgA Monoclonal Gammopathies of Undetermined Significance

Purpose: The presenting clinico-hematologic features of 1,283 patients with IgG and IgA monoclonal gammopathies of undetermined significance (MGUS) were correlated with the frequency of evolution into multiple myeloma (MM). Experimental Design: Two IgG MGUS populations were evaluated: a training sample (553 patients) and a test sample (378 patients); the IgA MGUS population consisted of 352 patients. Results: Forty-seven of the 553 training group patients and 22 of 378 test group IgG patients developed MM after a median follow-up of 6.7 and 3.6 years, respectively. Multivariate analysis showed that serum monoclonal component (MC) levels of ≤1.5 g/dL, the absence of light-chain proteinuria and normal serum polyclonal immunoglobulin levels defined a prognostically favorable subset of patients, and could be used to stratify the patients into three groups at different 10-year risk of evolution (hazard ratio, 1.0, 5.04, 11.2; P < 0.001). This scoring system was validated in the test sample. Thirty of the 352 IgA patients developed MM after a median follow-up of 4.8 years, and multivariate analysis showed that hemoglobin levels of <12.5 g/dL and reduced serum polyclonal immunoglobulin correlated with progression. A pooled statistical analysis of all of the patients confirmed the validity of Mayo Clinic risk model showing that IgA class, serum MC levels, and light-chain proteinuria are the most important variables correlated with disease progression. Conclusions: Using simple variables, we validated a prognostic model for IgG MGUS. Among the IgA cases, the possible prognostic role of hemoglobin emerged in addition to a decrease in normal immunoglobulin levels.

Importance of granulocyte colony-stimulating factor prophylaxis in therapy with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone given every 14 days for diffuse large B-cell lymphoma in routine clinical practice

1 Department of Haematology, Aalborg Hospital, Aalborg, Denmark, 2 Hematology, Henri Mondor Hospital, Creteil, France, 3 Department of Hematology, Erasmus MC, Rotterdam, The Netherlands, 4 Hematology Department, Hospital del Mar, Barcelona, Spain, 5 Division of Hematology and Hemostaseology, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria, 6 Haematology, St George ’ s University of London, London, UK, 7 UO Ematologia 1 – CTMO, Fondazione Policlinico MaRe IRCCS, Milano, Italy, 8 University Hospital, Leuven, Belgium, 9 Institute of Pharmaceutical Medicine, University of Basel, Basel, Switzerland, 10 AMLtd, London, UK and 11 Department of Hematology, University Hospital Essen, Essen, Germany

Darbepoetin alfa administration in patients with non-Hodgkin lymphoma and chemotherapy-induced anemia receiving (±R)CHOP

Abstract IMPACT NHL was a multicenter, observational study in adults with non-Hodgkin lymphoma receiving CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemotherapy with or without rituximab. Erythropoietin-stimulating agent treatment was given according to routine clinical practice and physician preference. In a subanalysis, outcomes were evaluated in 207 patients who received darbepoetin alfa (DA). The most common reason (81%) for initiating DA was low/declining hemoglobin (Hb) concentration. Mean (±standard deviation) duration of DA exposure was 8.8 ± 6.9 weeks (mean number of doses, 5.1 ± 4.6). Overall, 23% of patients had chemotherapy and DA treatment synchronized more than 75% of the time. At the time of DA initiation, 67% of patients had Hb concentrations in the guideline-recommended range (9–11 g/dl). Of 89 patients with Hb concentrations <10 g/dl at DA initiation and still receiving DA 5 weeks later, 92% (Kaplan–Meier) achieved Hb concentrations 10–12 g/dl between week 5 and at the end of treatment.