Anti-PD1 Consolidation in Patients with Hodgkin Lymphoma at High Risk of Relapse after Autologous Stem Cell Transplantation: A Multicenter Real-Life Study.

(1) Background: Consolidation therapy is an emerging strategy for patients with relapsed/refractory (RR) Hodgkin Lymphoma (HL) at high risk of failing salvage autologous stem cell transplantation (ASCT). (2) Objectives: To assess the safety and effectiveness of PD1-blockade consolidation for these high-risk patients. (3) Design: Multi-center retrospective analysis. (4) Methods: We identified 26 patients given anti-PD1 consolidation, from June 2016 to May 2020. (5) Results: Patients displayed the following risk factors: refractory disease (69%), relapse < 12 months from upfront therapy (15%), ≥2 lines of salvage therapy (73%), extranodal disease (65%). Nineteen patients (73%) had ≥3 of these factors. In addition, 16 patients (61%) also displayed PET-positive (Deauville ≥ 4) disease before ASCT. Treatment-related adverse events (TRAEs), never graded > 3, occurred in 12 patients (46.15%) and mainly included skin rashes (41.7%), transaminitis (33.3%), and thyroid hypofunction (25%). Patients completed a median of 13 courses (range 6−30). At a median follow-up of 25.8 months post-ASCT, the median progression-free (PFS) was 42.6 months, with a 2-year PFS and overall survival rates of 79% and 87%, respectively. (6) Conclusions: Post-ASCT consolidation with anti-PD1 is feasible and effective. Further studies are warranted to define the optimal treatment length and patients' subsets more likely to benefit from this approach.

Post-exposure prophylaxis with sotrovimab for Omicron (B.1.1.529) SARS-CoV-2 variant during the aplastic phase of autologous stem cell transplantation.

BACKGROUND: To date, there is no information on the safety and efficacy of the novel anti-sarbecoviruses monoclonal antibody sotrovimab administered, as a post-exposure prophylactic measure, during the aplastic phase of autologous stem cell transplantation (ASCT). METHODS: We describe the outcomes of a Multiple Myeloma (MM) patient, who was threateningly exposed to the Omicron (B.1.1.529) SARS-CoV-2 variant, two days after having received a myeloablative regimen of high-dose melphalan. The patient fulfilled all CDC criteria for prolonged close contacts with an index patient who tested positive for a molecular nasopharyngeal swab (Omicron; B.1.1.529) soon after admission to the ward. Given the high risks of morbidity and mortality in the case of COVID-19 developing during the aplastic phase of transplantation, we adopted a post-exposure prophylaxis intervention based on intravenous (i.v.) sotrovimab. RESULTS: Sotrovimab (500 mg i.v.) was administered at day + 2 from stem cells reinfusion, i.e. 4 days after myeloablative chemotherapy, and at day + 5 from the last close contact with the Omicron-positive index case. The patient was fully protected from SARS-CoV-2 infection throughout his clinical course and remained molecularly negative at the day + 30 from the transplant. We compared times to engraftment and transplant-related toxicities of the sotrovimab-treated patient with the last 15 MM patients transplanted at our Centre, evidencing no unexpected safety signals, infusion-related reactions, or alarming effects on engraftment kinetics. CONCLUSIONS: We have shown here for the first time that administration of sotrovimab during the pre-engraftment phase of ASCT is effective, safe, and not associated with delays in hemopoietic recovery. As compared to MM patients who received the same myeloablative conditioning regimen, the patient given sotrovimab during the aplastic phase did not show any significant differences in engraftment kinetics and toxicity outcomes. Post-exposure prophylaxis with sotrovimab may represent a valuable approach in the stem cell transplantation setting for patients with high-risk exposure to a confirmed COVID-19 case sustained by highly infectious SARS-CoV-2 variants escaping the vaccine-derived immunity due to antigenic shifts in the spike proteins.

Elotuzumab plus lenalidomide and dexamethasone in relapsed/refractory multiple myeloma: Extended 3-year follow-up of a multicenter, retrospective clinical experience with 319 cases outside of controlled clinical trials.

The combination of elotuzumab, lenalidomide, and dexamethasone (EloRd) enhanced the clinical benefit over Rd with a manageable toxicity profile in the ELOQUENT-2 trial, leading to its approval in relapsed/refractory multiple myeloma (RRMM). The present study is a 3-year follow-up update of a previously published Italian real-life RRMM cohort of patients treated with EloRd. This revised analysis entered 319 RRMM patients accrued in 41 Italian centers. After a median follow-up of 36 months (range 6-55), 236 patients experienced disease progression or died. Median progression-free survival (PFS) and overall survival (OS) were 18.4 and 34 months, respectively. The updated multivariate analyses showed a significant reduction of PFS and OS benefit magnitude only in cases with International Staging System stage III. Major adverse events included grade 3/4 neutropenia (18.5%), anemia (15.4%), lymphocytopenia (12.5%), and thrombocytopenia (10.7%), while infection rates and pneumonia were 33.9% and 18.9%, respectively. No new safety signals with longer follow-up have been observed. Of 319 patients, 245 (76.7%) reached at least a partial remission. A significantly lower response rate was found in patients previously exposed to lenalidomide. In conclusion, our study confirms that EloRd is a safe and effective regimen for RRMM patients, maintaining benefits across multiple unfavorable subgroups.

Atypical COVID-19 dynamics in a patient with mantle cell lymphoma exposed to rituximab.

Patients with non-hodgkin lymphomas (NHL) represent a population of special interest during the current Coronavirus disease-19 (COVID-19) pandemics. NHLs are associated with disease- and treatment-related immunodeficiencies which may generate unusual COVID-19 dynamics and pose unique management challenges. We report the unusual clinical course of COVID-19 in a patient with mantle cell lymphoma (MCL) exposed to nine doses of Rituximab shortly before infection with severe acute respiratory syndrome corona virus 2 (SARS-CoV-2). He had a prolonged asymptomatic phase, with negative molecular and antibody testing for SARS-CoV-2, followed by a rapidly progressive evolution to severe COVID-19. Despite detection of viral RNA overlapped with first symptoms occurrence, anti-SARS-CoV-2 antibodies displayed an asynchronous pattern, with IgG first appearing 2 days after RNA positivity and IgM never being detected throughout the entire clinical course. While disease-associated immune derangements and/or previous treatments involving anti-CD20 antibodies might have contributed to COVID-19 dynamics in our patient, data suggests that antibody testings, without concurrent molecular assessment for SARS-CoV-2, may turn inadequate for monitoring of MCL patients, and in general NHL patients heavily exposed to anti-CD20 antibodies, during the current pandemics. We suggest that repeated molecular testing of nasopharyngeal swab should be implemented in these subjects despite a negative serology and absence of symptoms of SARS-CoV-2 infection. For the same reasons, a customized strategy needs to be developed for patients exposed to anti-CD20 antibodies, based on different features and mechanism of action of available SARS-CoV-2 vaccines and novel vaccinomics developments.

Improved outcome of patients with relapsed/refractory Hodgkin lymphoma with a new fotemustine-based high-dose chemotherapy regimen.

High-dose chemotherapy (HDT) with autologous stem cell transplantation is the standard of care for relapsed/refractory (RR) Hodgkin lymphoma (HL). Given that HDT may cure a sizeable proportion of patients refractory to first salvage, development of newer conditioning regimens remains a priority. We present the results of a novel HDT regimen in which carmustine was substituted by a third-generation chloroethylnitrosourea, fotemustine, with improved pharmacokinetics and safety (FEAM; fotemustine, etoposide, cytarabine, melphalan) in 122 patients with RR-HL accrued into a prospective registry-based study. Application of FEAM resulted in a 2-year progression-free survival (PFS) of 73·8% [95% confidence interval (CI), 0·64-0·81] with median PFS, overall survival and time to progression yet to be reached. The 2-year risk of progression adjusted for the competitive risk of death was 19·4% (95% CI, 0·12-0·27) for the entire patient population. Most previously established independent risk factors, except for fluorodeoxyglucose ((18) (F) FDG)-uptake, were unable to predict for disease progression and survival after FEAM. Although 32% of patients had (18) (F) FDG-positrin emission tomography-positive lesions before HDT, the 2-year risk of progression adjusted for competitive risk of death was 19·4% (95% CI; 0·12-0·27). No unusual acute toxicities or early/late pulmonary adverse events were registered. FEAM emerges as an ideal HDT regimen for RR-HL patients typically pre-exposed to lung-damaging treatments.

High-Dose Melphalan Plus Thiotepa as Conditioning Regimen before Second Autologous Stem Cell Transplantation for "De Novo" Multiple Myeloma Patients: A Phase II Study.

High-dose melphalan (MEL) is the standard therapy for autologous stem cell transplantation (ASCT) in multiple myeloma (MM), although the optimal conditioning regimen remains yet to be identified. Thiotepa (THIO) appears to be a potentially effective option, with broad-spectrum antitumor efficacy that can be added to myeloablative multiagent regimens for ASCT in hematopoietic tumors. We conducted a phase II trial, adding THIO (275 mg/m(2)) to high-dose MEL (140 mg/m(2)) before a second ASCT, in a tandem ASCT strategy, in 64 patients with "de novo" MM. Overall, there was no transplant-related mortality. The incidence of neutropenic fever and mucositis (grades 3 to 4) was 39% and 9%, respectively. Median number of days to neutrophil and platelet engraftment were 11 and 12, respectively. After the second transplantation, the complete response improved to 43.8%. Overall response rate was 86%. After a median follow-up of 18.1 months, 13 patients had progressed and 3 died from MM. Median progression-free survival was not reached, and actuarial 2-year rates of progression-free and overall survival were 71% and 88.9%, respectively. Our results suggest that THIO/MEL is a feasible and safe conditioning regimen for ASCT in MM and should be explored for efficacy in a phase III study.

Use of allogeneic platelet gel in the management of chemotherapy extravasation injuries: a case report.

The allogeneic platelet (PLT) gel offers to be a valid supportive measure in the management of chemotherapy extravasation injuries. We report a case of a 58-year-old patient with multiple myeloma enrolled for high-dose chemotherapy and autologous stem cell transplantation. As pretransplant therapy, the patient received induction therapy with bortezomib, adriblastina, and desametazone. A port was inserted in the vein on the back of the hand. After three cycles, the patient reported rapid development of redness, pain, and necrotic tissue in the left hand, and a diagnosis of extravasation was addressed. The patient presented a raw area on the back of the hand caused by cytotoxic/chemotherapeutic drug leakage because of the malposition of venous access devices. Skin ulcer was debrided, and the wound was reconstructed with a combination of local random rotational flap and abdomen skin graft. Two weeks later, a 20% skin flap necrosis was observed. In the context of wound healing, topical plasma-rich PLT gel is able to accelerate the regeneration and repair of tissue, so it was set out to assess PLT gel efficacy in this case. The PLT gel was applied topically once every 5 days, for a duration of 60 days on average. There were no adverse reactions observed during the topical therapy. Complete wound healing was observed after 12 PLT-rich plasma applications. No ulcer recurrence was noted in the patient during the follow-up period of 2-19 months.

A phase II study of dose-dense and dose-intense ABVD (ABVDDD-DI ) without consolidation radiotherapy in patients with advanced Hodgkin lymphoma.

We explored activity and safety of a dose-dense/dose-intense adriamycin, bleomycin, vinblastine and dacarbazine regimen (ABVDDD-DI ) in 82 patients with advanced Hodgkin Lymphoma. Patients entered a two-stage Bryant-Day Phase II study to receive six cycles of ABVDDD-DI without consolidation radiotherapy. Cycles were supported with granulocyte colony-stimulating factor and delivered every 21 d; drugs were administered on days 1 and 11 at the same doses of standard ABVD except for doxorubicin (35 mg/m2; first four cycles only). Co-primary endpoints were complete response (CR) rate and severe acute cardiopulmonary toxicity; secondary endpoints were event-free (EFS) and disease-free survival (DFS). All patients received the four doxorubicin-intensified courses and 96% concluded all six cycles (82.3% within the intended 18 weeks). This translated into a 66.9% increase of received dose-intensity for doxorubicin and 31.8% for the other agents over standard ABVD. The CR rate was 95.1% (78/82) and 87.8% (72/82) achieved a metabolic CR after two cycles. Cardiopulmonary toxicity never exceeded grade 2 and affected 14.6% of patients. Most frequent toxicities were grade 4 neutropenia (10%) and anaemia (9%), grade 3 infection (17%) and grade 2 mucocutaneous changes (30%). Five-year EFS and DFS was 88.3% and 93.7%, respectively. ABVDDD-DI regimen was well-tolerated and ensured substantial CR and EFS rates without radiotherapy.

Efficacy and safety of the third-generation chloroethylnitrosourea fotemustine for the treatment of chemorefractory T-cell lymphomas.

Patients with recurring T-cell non-Hodgkin lymphoma (T-NHL) are incurable and candidate for investigational agents. Here, we report on five patients with T-NHL refractory to multiple chemotherapy lines, including in all cases alkylators and gemcitabine, who received the third-generation chloroethylnitrosourea fotemustine at a dose of 120 mg/m(2) every 21 d, up to eight courses. Median actual dose intensity was 79%; toxicity was manageable and mainly hematological. One complete remission, one partial remission, two protracted disease stabilization, and one transient, minor response were achieved. Time to progression ranged from 48 to 240+ d. This is the first evidence ever reporting the activity of fotemustine in end-stage T-NHL. Formal studies with this agent are warranted in T-cell malignancies.

Biweekly rituximab, cyclophosphamide, vincristine, non-pegylated liposome-encapsulated doxorubicin and prednisone (R-COMP-14) in elderly patients with poor-risk diffuse large B-cell lymphoma and moderate to high 'life threat' impact cardiopathy.

This Phase II study assessed feasibility and efficacy of a biweekly R-COMP-14 regimen (rituximab, cyclophosphamide, non-pegylated liposome-encapsulated doxorubicin, vincristine and prednisone) in untreated elderly patients with poor-risk diffuse large B-cell lymphoma (DLBCL) and moderate to high 'life threat' impact NIA/NCI cardiac comorbidity. A total of 208 courses were delivered, with close cardiac monitoring, to 41 patients (median age: 73years, range: 62-82; 37% >75years) at a median interval of 15·6 (range, 13-29) days; 67% completed all six scheduled courses. Response rate was 73%, with 68% complete responses (CR); 4-year disease-free survival (DFS) and time to treatment failure (TTF) were 72% and 49%, respectively. Failures were due to early death (n=3), therapy discontinuations (no-response n=2; toxicity n=6), relapse (n=6) and death in CR (n=3). Incidence of cardiac grade 3-5 adverse events was 7/41 (17%; 95% confidence interval: 8-31%). Time to progression and overall survival at 4-years were 77% and 67%, respectively. The Age-adjusted Charlson Comorbidity Index (aaCCI) correlated with failures (P=0·007) with patients scoring ≤7 having a longer TTF (66% vs. 29%; P=0·009). R-COMP-14 is feasible and ensures a substantial DFS to poor-risk DLBCL patients who would have been denied anthracycline-based treatment due to cardiac morbidity. The aaCCI predicted both treatment discontinuation rate and TTF.

Long-term results of gemcitabine plus oxaliplatin with and without rituximab as salvage treatment for transplant-ineligible patients with refractory/relapsing B-cell lymphoma.

PURPOSE: To determine the efficacy and safety of the combination of gemcitabine plus oxaliplatin, with and without rituximab, in patients with relapsed/refractory B-cell lymphoma unsuitable for high dose therapy. METHODS: Patients were prospectively enrolled in two subsequent trials, GEMOX [gemcitabine (1200 mg/m(2), days 1 and 8) and oxaliplatin (120 mg/m(2), day 2), three-weekly] and R-GEMOX [rituximab (375 mg/m(2), day 1), gemcitabine (1200 mg/m(2), day 1) and oxaliplatin (120 mg/m(2), day 2), bi-weekly], up to six courses. RESULTS: Sixty-two patients were enrolled: GEMOX [n = 30; median age, 66 years (range, 46-85); previous chemotherapy > or =2, 70%; PS ECOG > or = 2, 57%]; R-GEMOX [n = 32; median age, 65 years (range 32-79); previous chemotherapy > or =2, 75%; PS ECOG > or = 2, 47%]. Overall and complete response rates were 57 and 30% (95% CI, 15-49) for GEMOX and 78 and 50% (95% CI, 32-68) in R-GEMOX, respectively. Grade 3/4 neutropenia occurred in 57 and 47% of cycles and grade 3/4 thrombocytopenia in 26 and 17% of courses for GEMOX and R-GEMOX, respectively. At 42 months, the failure-free survival (FFS) was 7% (95% CI, 0-16) for GEMOX and 28% (95% CI, 9-47) for R-GEMOX (P = 0.014), with overall survivals of 7 (95% CI, 0-16) and 37% (95% CI, 20-55), respectively (P = 0.016). CONCLUSIONS: Both regimes showed good tolerability and appealing response rates. FFS was more prolonged in R-GEMOX, but patients continuously relapsed without a clear plateau on survival curves.

Rituximab therapy for chronic lymphocytic leukemia-associated autoimmune hemolytic anemia.

Autoimmune hemolytic anemia (AIHA) is a well-known complication of chronic lymphocytic leukemia (CLL). In recent years the anti-CD20 monoclonal antibody rituximab has been used for the therapy of steroid-refractory AIHA and autoimmune thrombocytopenia, either idiopathic or in association with CLL. We report the results of rituximab treatment for 14 patients suffering from CLL-associated AIHA. They developed a direct antiglobulin test positive AIHA at a mean time of 47 months (range 0-135 months) from the diagnosis of CLL. In 3 cases AIHA was diagnosed at the same time as CLL. Only 1 patient had fludarabine-related AIHA. All patients received steroids as first-line treatment. At a mean time of 46 days (range 1-210 days) from the diagnosis of AIHA all patients received rituximab at a dosage of 375 mg/m(2)/weekly for 4 weeks. All patients except 3 (2 died of cardiac failure or sepsis soon after the third cycle and 1 HCV-positive patient experienced a rise in serum amino transferases) completed the scheduled four programmed cycles. First injection side effects of rituximab were minimal. All but 2 patients showed an increase in hemoglobin levels in response to rituximab (mean value 3.6 g/dl; range 0.7-10 g/dl) and a reduction in the absolute lymphocyte count and lymph nodes and spleen volume. Nine patients required packed red cell transfusions before starting rituximab; 5 no longer needed transfusions just after the second cycle and another patient after the fourth cycle. Three patients (22%) were considered to fully respond and 7 (50%) only responded partially. At a mean follow-up of 17 months, 8 patients were still alive, 6 of them transfusion-free. Our results prove that the anti-CD20 monoclonal antibody is an effective and well-tolerated alternative treatment for CLL-associated AIHA.