Davide Nappi

Ruxolitinib rechallenge in combination with hydroxyurea is effective in reverting cachexia and reducing blood transfusion demand and splenomegaly symptoms in a patient with primary myelofibrosis

Dear Editor, Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) whose pathogenesis mainly involves JAK/STAT signaling; approximately 65% of patients carry V617F-JAK2 mutation with a gain-of-function mechanism [1, 2]. Hydroxyurea is recommended as the first-line therapy for MF in low and intermediate-1 patients, whereas ruxolitinib, an orally available and selective JAK2-inhibitor, is recommended in Internat ional Prognost ic Scor ing System (IPSS) intermediate-2 and high-risk patients as front-line treatment of symptoms and splenomegaly in non-transplant candidates [3]. We describe the case of a 57-year-old Caucasian man with primary MF (PMF). The patient was 166 cm in height and weighed 60 kg; before diagnosis, he had been in fair physical condition. At diagnosis (November 2012), his main symptoms were early satiety and a sense of fullness in the left upper abdomen that rapidly deteriorated into cachexia. His blood count showed anemia and leukocytosis, and a physical examination revealed splenomegaly (10 cm from costal margin); size measured by ultrasound scan [4] was 22 cm (longitudinal diameter) × 14 cm (transverse diameter) with a spleen volume of 2700 mL. Bone marrow biopsy demonstrated grade 3 fibrosis (MF = 3) and the presence of JAK2-V617Fmutation. In December 2012, cytoreductive therapy with hydroxyurea (1 and 2 capsules daily on alternate days) was started, obtaining a stable disease for fewmonths. After 3months, systemic symptoms and splenomegaly worsened. The patient was cachectic, his weight had fallen to 47 kg, and his spleen was of hard consistency and had enlarged, extending to the iliac fossa. He had lack of appetite, he was having difficulty eating, and his quality of life had deteriorated badly. The severity of the patient’s condition led to the consideration of other treatment options. The patient refused allogeneic stem cell transplantation after becoming aware of transplant-related risks and peritransplant mortality. Therefore, treatment with ruxolitinib was initiated, initially at 10 mg twice daily (bid), and reduced to 5 mg bid in response to grade 3 thrombocytopenia. The patient experienced only partial relief from symptoms and, in September 2014, ruxolitinib was discontinued due to severe leukocytosis and very poor compliance. After hydroxyurea was reintroduced to control leukocytosis, there was a considerable increase in the need for blood transfusions over subsequent months (up to 8 units/month; Fig. 1) and spleen size increased, reaching 27.8 cm longitudinal diameter. Following poor compliance with gastroprotective drugs, the patient required hospitalization in April 2015 for gastric bleeding, and hydroxyurea therapy was stopped due to severe anemia and thrombocytopenia (30,000/mm). Hydroxyurea was reintroduced with palliative intent after 1 month and, in June 2015, low-dose ruxolitinib (5 mg bid) rechallenge was undertaken, in combination with hydroxyurea (1 and 2 capsules daily on alternate days for 5 days/ week). The ruxolitinib dose was increased to 10 mg bid after 1 month, and after 2 months (September 2015), the patient * Claudio Cerchione claudiocerc@hotmail.com

Managing neutropenia by pegfilgrastim in patients affected by relapsed/refractory multiple myeloma treated with bendamustine-bortezomib-dexamethasone

Dear Editor, Febrile neutropenia (FN) is a serious side effect of chemotherapy, and even when it does not result in significant morbidity, mortality, and costs, it normally leads to a delay in subsequent chemotherapy treatments [1]. Suboptimal delivery of chemotherapy and reduced relative dose intensity (RDI) adversely affects long-term cancer outcome and survival [2]. FN is a surrogate marker for infections during chemotherapy and is characterized by an absolute neutrophil count (ANC) <1000/mmc and a single body temperature of >38.3 °C or a sustained temperature of ≥38 °C for more than 1 h [1, 3]. Risk of FN is dependent on both patient-specific factors (e.g., type of cancer, disease stage, co-morbid conditions, and age) and the myelotoxicity of the chemotherapy regimen. Once an episode of FN occurs, the risk of FN increases in subsequent chemotherapy cycles [4]. Recombinant granulocyte colony-stimulating factors (GCSFs) have been developed to stimulate proliferation and differentiation of neutrophils in patients receiving chemotherapy. The American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) recommend the use of G-CSF as primary prophylaxis (PP) when the overall FN risk is greater than 20 % following myelosuppressive chemotherapy, and secondary prophylaxis (SP) following FN or a dose-limiting neutropenic events [4, 5]. Pegfilgrastim is a pegylated long-acting recombinant form of G-CSF which extends the half-life, requiring less frequent dosing than non-pegylated G-CSF [6]. It is indicated to decrease the incidence of infection, as manifested by FN, in patients with non-myeloid malignancies receiving myelosuppressive chemotherapy associated with a clinically significant incidence of FN [5]. Pegfilgrastim is cleared via a neutrophilmediated system and requires only a single dose administered subcutaneously once per chemotherapy cycle [6–8]. Multiple myeloma (MM) in advanced phases of disease may be managed by regimens combining agents not frequently employed in early phases of treatment (e.g., anthracyclines, alkylating agents, etc), which have significant myelotoxicity. Bendamustine is a bifunctional alkylating agent that produces both single and double strand breaks in DNA, which has shown good results in association with bortezomib and dexamethasone in heavily pretreated patients [9], but in this schedule myelotoxicity is themainexpectedsideeffect [10]. In thiscontext, G-CSFs are often necessary to warrant an effective treatment, counteracting the risks of febrile neutropenia. Their use is bound to frequent evaluation of neutrophil counts which may not be easily performed by patients in home care. Avoiding severe neutropenia by prophylactic long-acting G-CSF, as pegfilgrastim, seems particularly useful in this setting of patients. The objective of this retrospective study was to evaluate the efficacy and safety of pegfilgrastim in relapsed and refractory MM patients, in treatment with courses of bendamustinebortezomib-dexamethasone (BVD), in order to determine whether primary prophylaxis with pegfilgrastim is more effective than that with filgrastim [6, 11–13] in terms of incidence of chemotherapy disruptions due to FN, days of hospitalization, and G-CSF-related extra-hematological side effects.

Bendamustine plus Rituximab Versus R‐CHOP as First‐Line Treatment for Patients with Follicular Lymphoma Grade 3A: Evidence from a Multicenter, Retrospective Study

BACKGROUND Rituximab plus bendamustine (R-B) has been demonstrated to improve outcomes and reduce toxicity compared with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHOP) in follicular lymphoma (FL). Nevertheless, in clinical practice, many centers still prefer R-CHOP to R-B in patients with FL grade 3A (FL3A). Therefore, we retrospectively assessed patients with FL3A treated with either R-CHOP or R-B in five European cancer centers and compared their outcomes. MATERIALS AND METHODS We retrospectively assessed 132 patients affected by FL grade 3A treated with either R-B or R-CHOP in the first line and evaluated outcome and toxicity according to the type of treatment. This study included 101 patients who were a subgroup of a previously published cohort. RESULTS R-B was less toxic and achieved a similar percentage of complete remissions compared with R-CHOP (97% vs. 96%, p = .3). During follow-up, 10 (16%) patients relapsed after R-B and 29 (41%) after R-CHOP (p = .001), leading to a median progression-free survival (PFS) of 15 versus 11.7 years, respectively (p = .03). Furthermore, R-B overcame the negative prognostic impact of BCL2 expression (15 vs. 4.8 years; p = .001). However, median overall survival was similar between both groups (not reached for both; p = .8). CONCLUSION R-B as a first-line treatment of FL3A is better tolerated than R-CHOP and seems to induce more profound responses, leading to a significantly lower relapse rate and prolonged PFS. Therefore, R-B is a valid treatment option for FL grade 3A. IMPLICATIONS FOR PRACTICE Rituximab plus bendamustine (R-B) has shown to be less toxic and more effective than rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHOP) in follicular lymphoma grade 3A. Although both regimens can induce a complete remission in >95% of patients, relapses occur more frequently after R-CHOP than R-B, leading to a significantly longer progression-free survival in the latter. R-B is also able to overcome the impact of negative prognosticators, such as BCL2 expression. However, because of the indolent course of this disease and efficient salvage treatments, overall survival was similar in both treatment groups. Therefore, R-B is a valid treatment option in this patient setting.

Safety and comfort of domestic bortezomib injection in real-life experience

Despite novel agents, multiple myeloma is still an incurable disease, especially for elderly and frail patients, who are difficult to manage for concomitant comorbidities as the therapeutic options are limited and the response to chemotherapy is often short. We report our evaluations upon safety and efficacy of domestic subcutaneous bortezomib in elderly and frail patients candidate to bortezomib-melphalan-prednisone (VMP) regimen. We confirmed that overall incidence of adverse events, including peripheral neuropathy, was low, and in no case required admission to emergency service, contributing to reduce the rate of therapy discontinuation. These results confirm the effectiveness and safety of subcutaneous bortezomib, in a real-life-experience, and define a new possibility of safe auto-administration in a comfortable domestic setting. We suggest that domestic treatment can significantly improve the quality of life of the patients, avoiding unnecessary transfer to the hospital without reducing treatment efficacy.

Pomalidomide-Dexamethasone in the Management of Heavily Pretreated Multiple Myeloma

S256 duration of neutropenia (neutrophil count < 1.5 x 10 ˇ 9 cells/L), comparing pegfilgrastim and filgrastim. During pegfilgrastim, neutropenia was never longer than 8 days, with a consequent reduction of neutropenia-related infections. Median nadir neutrophil count, evaluated for every patients for at least three courses of therapy (r. 3-6) registered at day +11, was 1.37 (range 0.9-2.1 x 10 ˇ 9 cells/L); only 4 patients (13.7%) needed, one week after pegfilgrastim administration, a supplement of 3 administrations of filgrastim. During pegfilgrastim prophylaxis, neutropenia was shorter than during Filgrastim treatment. Besides the mono-administration, pegfilgrastim was well tolerated in all patients: main side effects in our patients were mild fever and bone pain, (6/29 patients, 20.6%). Conclusions: In conclusion, in patients affected by heavily pretreated MM treated with pomalidomide-dexamethasone, pegfilgrastim seems to reduce the incidence of severe neutropenia and infections and may increase the possibility to maintain the scheduled time of treatment.

A case of efficacy of bendamustine in heavily pretreated multiple myeloma, refractory to pomalidomide

In this report, we would like to highlight the efficacy of bendamustine in a heavily pretreated patient, also refractory to pomalidomide. It is conceivable that different therapy combinations in heavily treated Multiple myeloma (MM) have to be explored, without “a priori” exclusion of ancient drugs, even after failure of the ultimate pharmacological options.

Retreatment with Bendamustine-Bortezomib-Dexamethasone in a Patient with Relapsed/Refractory Multiple Myeloma

The clinical management of relapsed/refractory multiple myeloma and the correct choice of the most suitable therapy in heavily pretreated and fragile patients are tough clinical issues for clinicians. In advanced phases of disease, the choice of available therapies becomes very poor, and the retreatment with previously adopted and effective therapy, although unpredictable, could be an effective option. In this report, we describe the clinical history of a patient, previously treated with 9 lines of therapy, refractory to bortezomib and IMIDs, for whom the retreatment with bendamustine resulted in a stable disease with good quality of life.