A real-life study of daratumumab-bortezomib-dexamethasone (D-VD) in lenalidomide exposed/refractory multiple myeloma patients: a report from the Triveneto Myeloma Working Group.

Treatment of lenalidomide refractory (Len-R) multiple myeloma (MM) patients still represents an unmet clinical need. In the last years, daratumumab-bortezomib-dexamethasone (D-VD) combination was extensively used in this setting, even though only a small fraction of Len-R patients was included in the pivotal trial. This real-life study aimed to evaluate the efficacy and safety of the D-VD regimen in a cohort that exclusively enrolled Len exposed or refractory MM patients. The study cohort included 57 patients affected by relapsed/refractory MM. All patients were previously exposed to Len, with 77.2% being refractory. The overall response rate (ORR) was 79.6% with 43% of cases obtaining at least a very good partial response (VGPR). The D-VD regimen showed a favorable safety profile, with low frequency of grade 3-4 adverse events, except for thrombocytopenia observed in 21.4% of patients. With a median follow-up of 13 months, median progression-free survival (PFS) was 17 months. No significant PFS differences were observed according to age, ISS, LDH levels, type of relapse, and high-risk FISH. Len exposed patients displayed a PFS advantage as compared to Len refractory patients (29 vs 16 months, p = 0.2876). Similarly, patients treated after Len maintenance showed a better outcome as compared to patients who had received a full-dose Len treatment (23 vs 13 months, p = 0.1728). In conclusion, our real-world data on D-VD combination showed remarkable efficacy in Len-R patients, placing this regimen as one of the standards of care to be properly taken into account in this MM setting.

Elotuzumab plus pomalidomide and dexamethasone in relapsed/refractory multiple myeloma: a multicenter, retrospective, real-world experience with 200 cases outside of controlled clinical trials.

In the ELOQUENT-3 trial, the combination of elotuzumab, pomalidomide and dexamethasone (EloPd) proved to have a superior clinical benefit over pomalidomide and dexamethasone with a manageable toxicity profile, leading to its approval for the treatment of patients with relapsed/refractory multiple myeloma (RRMM) who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor. We report here a real-world experience of 200 cases of RRMM treated with EloPd in 35 Italian centers outside of clinical trials. In our dataset, the median number of prior lines of therapy was two, with 51% of cases undergoing autologous stem cell transplant and 73% having been exposed to daratumumab. After a median follow-up of 9 months, 126 patients had stopped EloPd, most of them (88.9%) because of disease progression. The overall response rate was 55.4%, a finding in line with the pivotal trial results. Regarding adverse events, the toxicity profile in our cohort was similar to that in the ELOQUENT-3 trial, with no significant differences between younger (<70 years) and older patients. The median progression-free survival was 7 months, which was shorter than that observed in ELOQUENT-3, probably because of the different clinical characteristics of the two cohorts. Interestingly, International Staging System stage III disease was associated with worse progression-free survival (hazard ratio=2.55). Finally, the median overall survival of our series was shorter than that observed in the ELOQUENT-3 trial (17.5 vs. 29.8 months). In conclusion, our real-world study confirms that EloPd is a safe and possible therapeutic choice for patients with RRMM who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor.

The power of telemedicine to improve CAR-T cell therapy programs: lessons learned from COVID-19 pandemic.

PURPOSE: CAR-T programs will burden increasingly on healthcare systems, since the implementation of these therapies involves: multidisciplinary team collaboration, post-infusion hospitalization with risk of life-threatening toxicities, frequent in hospital visits and prolonged follow-up which heavily influence patients' quality of life. In this review we propose an innovative, telehealth-based, model for monitoring CAR-T patients: this method was used for managing a case of COVID-19 infection occurred two weeks after CAR-T cell infusion. METHODS: Several benefits for management of all these aspects of CAR-T programs could be made using telemedicine: for example, telemedicine real-time clinical monitoring could reduce the COVID-19 contagion risks for CAR-T patients. RESULTS: Our experience confirmed feasibility and utility of this approach in a real-life case. We believe that use of telemedicine for CAR-T patients could improve: the logistics of toxicity monitoring (frequent vital sign checks and neurologic assessments), the multidisciplinary team communication (patient selection, specialists consulting, coordination with pharmacists, etc.), the decrease in hospitalization time and the reduction of ambulatory visits. CONCLUSIONS: This approach will be fundamental for future CAR-T cell program development, enhancing patients' quality of life and cost-effectiveness for healthcare systems.

Coexistence of TEMPI syndrome and leukocytoclastic vasculitis successfully treated with autologous stem cell transplantation.

The TEMPI syndrome is a very rare paraneoplastic syndrome associated with plasma cell dyscrasia and monoclonal gammopathy. First described in 2011, the pathophysiology of TEMPI syndrome is still unknown. Essential for diagnosis is to recognize the five clinical findings: telangiectasias, erythrocytosis and elevated serum erythropoietin, monoclonal gammopathy, perinephric fluid collection, and intrapulmonary shunting. Here we report a case of a woman with the coexistence of TEMPI and leukocytoclastic vasculitis, shedding light on a possible common inflammatory pathway involved in the pathogenesis of the syndrome.

Chimeric Antigen Receptor T-Cell Therapy: What We Expect Soon.

The treatment landscape for hematologic malignancies has changed since the recent approval of highly effective chimeric antigen receptor T-cell therapies (CAR-T). Moreover, more than 600 active trials are currently ongoing. However, early enthusiasm should be tempered since several issues are still unsolved and represent the challenges for the coming years. The lack of initial responses and early relapse are some hurdles to be tackled. Moreover, new strategies are needed to increase the safety profile or shorten the manufacturing process during CAR-T cells therapy production. Nowadays, most clinically evaluated CAR-T cells products are derived from autologous immune cells. The use of allogeneic CAR-T cells products generated using cells from healthy donors has the potential to change the scenario and overcome many of these limitations. In addition, CAR-T cells carry a high price tag, and there is an urgent need to understand how to pay for these therapies as many of today's current payment systems do not feature the functionality to address the reimbursement gap. Finally, the clinical experience with CAR-T cells for solid tumors has been less encouraging, and development in this setting is desirable.

Pegfilgrastim in Supportive Care of Hodgkin Lymphoma.

Neutropenia and febrile neutropenia are common and potentially life-threating events associated with chemotherapy treatment in Hodgkin lymphoma (HL). Neutropenia-related infectious events could be an issue both for direct clinical consequences and for delay in treatment delivery, affecting final outcomes in a potentially highly curable disease. Pegfilgrastim is the pegylated form of filgrastim, the recombinant form of human G-CSF, capable of prevent and mitigate neutropenic effects of chemotherapy, when adopted as primary prophylaxis in several hematological malignancies. No updated version of major international guidelines provides clear indication on prophylaxis use of pegfilgrastim in HL to prevent febrile neutropenia episodes in HL. Moreover, to date, scarce and non-uniform clinical experiences evaluating pegfilgrastim as prophylaxis in HL are present in the literature. Herein, we propose a brief summary of the literature data about efficacy and safety of the use of pegfilgrastim as primary prophylaxis in HL during chemotherapy treatment.

Therapeutic Targeting of Acute Myeloid Leukemia by Gemtuzumab Ozogamicin.

Acute myeloid leukemia (AML) is a complex hematological malignancy characterized by genetic and clinical heterogeneity and high mortality. Despite the recent introduction of novel pharmaceutical agents in hemato-oncology, few advancements have been made in AML for decades. In the last years, the therapeutic options have rapidly changed, with the approval of innovative compounds that provide new opportunities, together with new challenges for clinicians: among them, on 1 September, 2017 the Food and Drug Administration granted approval for Gemtuzumab Ozogamicin (GO) in combination with daunorubicin and cytarabine for the treatment of adult patients affected by newly diagnosed CD33+ AML. Benefits of GO-based regimens were also reported in the pre- and post-transplantation settings. Moreover, several biomarkers of GO response have been suggested, including expression of CD33 and multidrug resistance genes, cytogenetic and molecular profiles, minimal residual disease and stemness signatures. Among them, elevated CD33 expression on blast cells and non-adverse cytogenetic or molecular risk represent largely validated predictors of good response.

Pegfilgrastim for primary prophylaxis of febrile neutropenia in multiple myeloma.

Multiple myeloma (MM) survival rates have been substantially increased thanks to novel agents that have improved survival outcomes and shown better tolerability than treatments of earlier years. These new agents include immunomodulating imide drugs (IMiD) thalidomide and lenalidomide, the proteasome inhibitor bortezomib (PI), recently followed by new generation IMID pomalidomide, monoclonal antibodies daratumumab and elotuzumab, and next generation PI carfilzomib and ixazomib. However, even in this more promising scenario, febrile neutropenia remains a severe side effect of antineoplastic therapies and can lead to a delay and/or dose reduction in subsequent cycles. Supportive care has thus become key in helping patients to obtain the maximum benefit from novel agents. Filgrastim is a human recombinant subcutaneous preparation of G-CSF, largely adopted in hematological supportive care as "on demand" (or secondary) prophylaxis to recovery from neutropenia and its infectious consequences during anti-myeloma treatment. On the contrary, pegfilgrastim is a pegylated long-acting recombinant form of granulocyte colony-stimulating factor (G-CSF) that, given its extended half-life, can be particularly useful when adopted as "primary prophylaxis," therefore before the onset of neutropenia, along chemotherapy treatment in multiple myeloma patients. There is no direct comparison between the two G-CSF delivery modalities. In this review, we compare data on the two administrations' modality, highlighting the efficacy of the secondary prophylaxis over multiple myeloma treatment. Advantage of pegfilgrastim could be as follows: the fixed administration rather than multiple injections, reduction in neutropenia and febrile neutropenia rates, and, finally, a cost-effectiveness advantage.

Can early switch to rituximab-bendamustine in a patient with follicular non-Hodgkin lymphoma progressing during R-CHOP be considered frontline treatment?: A case report.

RATIONALE: Follicular non-Hodgkin lymphoma (fNHL) is a neoplasm characterized by an indolent course and chemosensitivity, but also by disease recurrence. Bendamustine is often used as frontline treatment or second line. HEADING DIAGNOSIS:: fNHL. PATIENT CONCERNS: A 63-year-old Caucasian male with diagnosis of fNHL lymphoma underwent to cyclophosphamide, doxorubicin, vincristine, and prednisone associated with rituximab chemoimmunotherapy, during which interim reevaluation showed progressive disease and severe toxicity. INTERVENTIONS: Early switch to rituximab-bendamustine. OUTCOMES: This regimen was well tolerated, patient compliance was optimal, there were no delays in administration and no infectious episodes. An interim reevaluation after 3 courses revealed that the patient was fit, the blood cell count was normal, and lymphadenopathies and nocturnal sweating had completely regressed. Of note, the PET/CT scan did not show fluorodeoxyglucose pathological uptake, clearly confirming disease regression. LESSONS: Early switching to a bendamustine-rituximab-based scheme, even during conventional chemotherapy, decreases toxicity and reduces the risk of treatment interruption or delay, with favorable effects on overall response and prognosis.

ABVD vs BEACOPP escalated in advanced-stage Hodgkin's lymphoma: Results from a multicenter European study.

The optimal first-line treatment for advanced-stage Hodgkin's lymphoma (HL) is still a matter of debate. While ABVD is less toxic and as effective as other, more intensive chemotherapy regimens, escalated BEACOPP (BEACOPPesc) is superior to ABVD for initial disease control and prolonged time-to-relapse. However, this advantage is associated with higher rate of early and late toxicities. As most of these data have been accumulated from clinical trials, a retrospective analysis was conducted in a large database of patients treated outside clinical trials to investigate the advantages and disadvantages of these regimes in a real-world setting. From October 2009 to October 2018, 397 advanced-stage HL patients treated with either ABVD or BEACOPPesc were retrospectively assessed in 7 European cancer centers (2 Austrian and 5 Italian centers). Complete metabolic remission (CMR) by PET was achieved in 76% and 85% of patients in the ABVD and BEACOPPesc groups, respectively (p = .01). Severe adverse events occurred more frequently with BEACOPPesc than ABVD. At a median follow-up of 8 years, 9% of the patients who achieved CMR after BEACOPPesc relapsed compared to 16.6% in the ABVD group (p = .043). No statistical difference in progression free survival (PFS) was observed between the two cohorts overall (p = .11), but there was a trend towards a superior PFS in high-risk patients treated with BEACOPPesc (p = .074). Nevertheless, overall survival was similar between the two groups (p = .94). In conclusion, we confirm that ABVD is an effective and less toxic therapeutic option for advanced-stage HL. Although BEACOPP results in better initial tumor control, the long-term outcome remains similar between the two regimens.

Combined Oral Fentanyl Citrate and Midazolam as Premedication for Bone Marrow Aspiration and Biopsy in Patients with Hematological Malignancies: A Randomized, Controlled and Patient-Blinded Clinical Trial.

Bone marrow aspiration and biopsy (BMAB) is a painful procedure, and the routinely used local infiltration anesthesia (LIA) with lidocaine is unable to provide pain relief during the most uncomfortable phases. The primary endpoint of the present randomized, patient-blinded trial was to evaluate the efficacy of an opioid and benzodiazepine combination plus LIA (sedoanalgesia) in patients undergoing BMAB for hematological malignancies. The secondary endpoint was the safety of the procedure in an outpatient setting. Ancillary assessments were anticipatory anxiety related to pain recall in the event of re-biopsy, and adequacy of bone tissue harvested. Patients were randomly assigned to one of 2 arms to receive either sedoanalgesic placebo plus LIA (standard group) or oral fentanyl citrate 200 µg plus oral midazolam 5 mg plus LIA (combo group) during BMAB. Pre-procedural anxiety and procedural pain were assessed according to the Numerical Rating Scale (NRS: 0-10), dividing the time of the procedure into five intervals (T0, T1, T2a, T2b and T3) and evaluating the degree of discomfort at each time (T) in both groups. One hundred and sixteen patients were eligible for the study. At T2b (time of biopsy) and T3 (time after biopsy), a significantly lower perception of pain was registered in the combo group. Moreover, there were no significant sedoanalgesia-related side-effects. Finally, histological specimens were higher in quality in the combo group. Sedoanalgesia was highly effective in reducing pain during biopsy, diminished anticipatory anxiety in patients undergoing re-biopsy and led to fewer non-diagnostic specimens being harvested.

Daratumumab for the Management of Newly Diagnosed and Relapsed/Refractory Multiple Myeloma: Current and Emerging Treatments.

Immunotherapy is changing the paradigm of multiple myeloma (MM) management and daratumumab is the first-in-class human monoclonal antibody targeting CD38 approved for the treatment of this malignancy. Daratumumab exerts anti-myeloma activity by different mechanisms of action as antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), complement-dependent cytotoxicity (CDC), direct apoptosis, and immunomodulation. After GEN501 and SIRIUS trials showed efficacy of daratumumab monotherapy in heavily pretreated relapsed-refractory multiple myeloma (RRMM), in patients with at least two previous line of therapy, two phase III trials demonstrated superior overall response rate (ORR) and progression free survival (PFS) using triplets daratumumab-bortezomib-dexamethasone (DVd) vs Vd (CASTOR) or daratumumab-lenalidomide-dexamethasone (DRd) vs Rd (POLLUX) in relapsed-refractory MM patients; so these combinations have been approved and introduced in clinical practice. The ongoing phase III CANDOR is evaluating the triplet daratumumab-carfilzomib-dexamethasone (DKd) vs Kd whereas phase III APOLLO trial is exploring daratumumab-pomalidomide-dexamethasone (DPd) vs PD. Many other trials exploring daratumumab combinations in relapsed-refractory MM are ongoing, and they will provide other interesting results. In newly diagnosed transplant-eligible patients, phase III CASSIOPEIA trial found the combination daratumumab-bortezomib-thalidomide-dexamethasone (Dara-VTd) significantly improves stringent Complete Response (sCR) rate and PFS compared with VTD, whereas in the phase II GRIFFIN study, comparing daratumumab-bortezomib-lenalidomide-dexamethasone (Dara-VRD) vs VRD, sCR rate was significantly higher using quadruplet combination. Many studies are evaluating daratumumab in consolidation and maintenance therapy after autologous stem cell transplantation (ASCT). As regard patients ineligible for ASCT, a great efficacy of daratumumab-containing combinations was reported by the phase III trials ALCYONE and MAIA, exploring daratumumab-bortezomib-melphalan-prednisone (DVMP) vs VMP and daratumumab-lenalidomide-dexamethasone (DRd) vs Rd, respectively. These studies provided results never seen before in this setting. The aim of this paper is to critically review the results obtained with regimens containing daratumumab both in relapsed-refractory and in newly diagnosed MM.

Adding hydroxyurea in combination with ruxolitinib improves clinical responses in hyperproliferative forms of myelofibrosis.

Ruxolitinib, an orally bioavailable and selective inhibitor of Janus kinase 1 (JAK1) and JAK2, significantly reduces splenomegaly and disease-related symptoms in patients with myelofibrosis (MF). However, no clear survival benefit has been demonstrated, which may in part reflect suboptimal drug exposure related to lower dosages needed to minimize hematological toxicity, specifically cytopenias. Furthermore, the optimal management of specific conditions such as leukocytosis or thrombocytosis in patients under ruxolitinib therapy is still undefined. In these cases, combining ruxolitinib with a cytoreductive agent like hydroxyurea might improve hematological response. This observational multi-center study enrolled 20 adult patients with intermediate- or high-risk primary MF, post- polycythemia vera MF, or postessential thrombocythemia MF with hyperproliferative manifestations of the disease and WBC and/or platelet counts not controlled by ruxolitinib therapy. The patients received treatment with a combination of ruxolitinib and hydroxyurea. A clinical response of any type was obtained in 8 patients (40%) during ruxolitinib monotherapy and in 17 patients (85%) during ruxolitinib-hydroxyurea combination (P = 0.003). After a median duration of 12.4 months of combination therapy, 16/20 patients had a hematological response; 14/17 patients who had started combination therapy to control WBC count and 2/3 who started in order to reduce platelets count. The number of patients requiring ruxolitinib dosage reduction or discontinuations was lower during combination therapy and, at the end of follow-up the median ruxolitinib dose was increased in 50% of patients. In conclusion, the combination of hydroxyurea with ruxolitinib yielded a high clinical response rate and increased ruxolitinib exposure in patients with hyperproliferative forms of MF.

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.

Lenalidomide at the dose of 25 mg every other day in patients affected by multiple myeloma and renal failure: a real-life experience.

Renal impairment (RI) is a relevant complication of patients affected by multiple myeloma (MM); it can be present in up to 30-35% of newly diagnosed MM and is linked to a poor outcome. However, early recognition and early treatment with novel agents can overcome the negative impact of RI and even reverse kidney damage in most cases. Lenalidomide, available as an oral compound, is an immunomodulatory drug with both antiproliferative and immunomodulatory activity that is largely used in the management of MM. Dose reduction is mandatory in RI; however, there is no theoretical assumption against the possibility that protracting the time of full standard doses can be equally effective and tolerated by patients requiring reduced doses. In this report, we describe our retrospective experience, in 18 patients, with the administration of lenalidomide 25 mg every other day for patients with MM and RI. The overall response ratio was 66.5%. More than half (61.1%) of the patients had a renal response. The median progression-free survival was 8 months (range: 3-18 months). No serious adverse event occurred during treatment, and it was never necessary to disrupt or delay treatment for toxicity. These preliminary observations point to a significant therapeutic effect of lenalidomide, at the dose of 25 mg every other day for 21 days, with logistic and economic advantages. However, these results should be validated by controlled studies involving larger numbers of patients.

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.

Secondary syphilis mimicking malignancy: A case report and review of literature.

A 56-year-old man developed disseminate lymphadenopathies, associated with hepato-splenomegaly, fever, nocturnal sweating and weight loss. Imaging studies in particular FDG-PET/CT raised the suspicion of a malignant disease. But blood flow cytometry assay for B/T cell clonality was negative and fine-needle biopsy of enlarged laterocervical lymph node showed a not specific "reactive hyperplasia". Four months later, the patient developed a non-itching rash; since a further anamnestic investigation revealed an history of high-risk sexual intercourse, the patient underwent serological tests for Treponema pallidum that were positive at high titer, after a first negative screening. Made the diagnosis of secondary syphilis, the patient responded to the treatment with benzyl penicillin with complete resolution of symptoms. This case highlights the importance of carefully screening the patients with suspected lymphoadenopathies also for lue, particularly in presence of behavioral risk factors.

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.