Search

The course of multiple myeloma (MM) is influenced by a variety of factors, including the specificity of the tumour microenvironment (TME). The aim of this review is to provide insight into the interplay of treatment modalities used in the current clinical practice and TME. Bortezomib-based triplets are the standard for MM first-line treatment. Bortezomib is a proteasome inhibitor (PI) which inhibits the nuclear factor kappa B (NF-kappa B) pathway. However, bortezomib is decreasing the expression of chemokine receptor CXCR4 as well, possibly leading to the escape of extramedullary disease. Immunomodulatory drugs (IMiDs), lenalidomide, and pomalidomide downregulate regulatory T cells (Tregs). Daratumumab, anti-cluster of differentiation 38 (anti-CD38) monoclonal antibody (MoAb), downregulates Tregs CD38+. Bisphosphonates inhibit osteoclasts and angiogenesis. Sustained suppression of bone resorption characterises the activity of MoAb denosumab. The plerixafor, used in the process of stem cell mobilisation and harvesting, block the interaction of chemokine receptors CXCR4-CXCL12, leading to disruption of MM cells' interaction with the TME, and mobilisation into the circulation. The introduction of several T-cell-based immunotherapeutic modalities, such as chimeric-antigen-receptor-transduced T cells (CAR T cells) and bispecific antibodies, represents a new perspective in MM treatment affecting TME immune evasion. The optimal treatment approach to MM patients should be adjusted to all aspects of the individual profile including the TME niche.

Background: Autoimmune hemolytic anemia (AIHA) is a rare autoimmune disease in which red blood cells (RBC) are targeted by autoantibodies confirmed with positive direct antiglobulin test (DAT), resulting in premature destruction of RBC. AIHA may be subdivided into warm antibody AIHA (wAIHA) and cold antibody AIHA (cAIHA), and also to primary and secondary depending on the presence of an underlying disorder. In addition to that, patients may have positive DAT but without features of hemolysis, and some of them will later develop AIHA. Aims: The aim of this study was to analyze characteristics of newly diagnosed DAT positive AIHA patients during the 5 years period in our tertiary center, as well to assess DAT positive patients without features of AIHA. Methods: This was a single-center retrospective cohort study performed at the University Hospital Center (UHC) Zagreb, Zagreb, Croatia, Department of Internal Medicine, Division of Hematology. We included data for all consecutive adult patients with a newly diagnosis of DAT positive AIHA between 2014 and 2018, and also all DAT positive patients without features of hemolysis in that time period. This study was approved by the UHC Ethical Committee. Descriptive statistics was performed and included means ± SD or median (range) as appropriate for continuous variables and frequency (percentage) for categorical variables. Results: The data from 56 patients (50% women) with newly diagnosed DAT positive AIHA during the study period were analyzed. The median age at time of AIHA diagnosis was 67 years (range 22–90 years). Majority of AIHA was wAIHA (51 (91.1%) patients). AIHA was considered primary in only 14 (25%) patients and was associated with an underlying disorder in 42 (75%) patients. The various disorders were associated with secondary wAIHA, the most frequently B-cell lymphoproliferative malignant diseases (33%), solid tumors (9.8%), myelodisplastic syndrome (9.8%) and autoimmune diseases (9.8%). Median hemoglobin level at the AIHA diagnosis was 71 g/L. 82.1% of patients received RBC transfusion. Seven (12.5%) patients did not require immunosuppressive treatment and other received mostly corticosteroids as the 1st line of therapy. Rituximab received 9 patients (17.6%) with wAIHA, mostly as the 2nd line of treatment. Eight patients (14.3%) with AIHA developed thrombosis (7 with wAIHA and 1 with cAIHA). During the 5-years study period additional 120 patients with DAT positive results but without signs of hemolysis were detected. Summary/Conclusion: Data from our 5-years single centre experience with AIHA are comparable with literature data. Majority of patients had secondary AIHA and wAIHA. Rituximab is used mostly as the second-line treatment and corticosteroid-sparing agent for wAIHA. Significant number of patients with DAT positive results but without features of hemolysis was detected, and they need to be closely monitored for possible development of AIHA.

We started using eBEACOPP for front-line treatment of cHL patients 15 years ago ; first within clinical trials, then in high-risk patients with advanced disease and finally in all younger than 60 except those with limited stage and favorable prognosis. Here we describe our experience. We treated 112 patients, 19–69 years old (median 29). Median fol low-up is 40 months. 5-year PFS is 94% and OS 97%. All patients were treated in an outpatient setting, with regular check ups or telephone contacts at least twice weekly. Toxicity during therapy was significant, 50% patients were hospitalized, mostly for infectious complications. Granulocytopenia gr. 4 occurred in 94%, anemia gr. 3–4 in 67% and trombocytopenia gr. 3–4 in 61% of patients. Non-he matological, non-infectious toxicity was rare ; 12% had neuropathy, most recovered. 2 patients developed allergy to etoposide. 3 patients died of toxicity ; 2 of infection, both failed to report early symptoms. The third died suddenly at home, probably due to pulmonary embo lism. All remaining patients responded to therapy ; 3 relapsed. 2 of the relapses occurred in areas that could have been irradiated. The 3rd was PET negative after 2 cycles of eBEACOPP, so treatment was stopped after the 4th. Slightly more than 50% of women resumed spontaneous menstrual cy cles. Other late toxicities were rare. Avascular hip necrosis decreased significantly after we stopped using methlyprednisolone and reduced the number of days on steroids to 8 per cycle. A single patient developed secondary cancer, acute myeloid leukemia. 2 patients have symptomatic heart disease, both were older than 60 at time of treatment and had mediastinal irradiation. In conclusion, eBEACOPP is a very effective and feasible outpatient reg imen for front-line treatment of patients with cHL younger than 60 pro vided it is delivered by a dedicated and experienced team. Acute toxicity is almost universal ; in order to avoid unnecessary deaths patients must be disciplined and have fast access to adequate medical care. Treatment reductions should only be performed after careful considerations. In pa tients interested in preserving fertility sperm cryopreservation should be offered to men and GnRH analogues to women. Other late toxicities are rare, and most cHL survivors treated with eBEACOPP are able to return to a normal and productive life.

When ABVD is used as the chemotherapy backbone for newly diag nosed cHL, patients with favorable stage I-II (EF), unfavorable stage I II (EU), favorable stage III-IV (Hasenclever index 0-2) (AF) and unfavor able stage III-IV (Hasenclever index ≥3) (AU) differ in EFS with the latter having the worst prognosis. GHLSG has reported that the intro duction of eBEACOPP-based chemotherapy for EU and advanced stage groups annuls this difference. To our knowledge, no other group has reproduced these findings. Since 2010, after the end of accrual into the EORTC 20012 trial, we recommend eBEACOPP as front-line therapy for AU. During 2014/5 this recommendation was extended to AF and EU patients. Here we analyze the outcome of different prognostic groups of newly diagnosed cHL patients below 60 years of age treated at our institution during the period of almost 5 years when eBEACOPP was used as initial treatment only for AU patients. There were 13 patients in the EF group, one was treated with ABVD only, one with radiotherapy (RT) only, and 11 with the combination of ABVD and RT. None relapsed or died. 38 patients were in the EU group. All started ABVD, two switched to eBEACOPP because of interim PET positivity ; 33 received RT and five chemother apy only. Two progressed immediately after RT, additional 8 relapsed, 2 died. EFS at three years was 72% and OS 97%. 20 patients were in the AF group. All received ABVD, three switched to eBEACOPP because of interim PET positivity ; four received additional RT. Two patients died, one due to sepsis after switching to eBEACOPP and one, treated with ABVD, due to bleomycin-related pneumonitis ; additional two relapsed. EFS at three years was 79% and OS 90%. 34 patients were in the AU group. 30 started treatment with eBEACOPP and 4 with ABVD, one switched to eBEACOPP because of interim PET pos itivity ; 10 received additional RT. One patient died during treatment, presumably due to pulmonary embolism ; one relapsed. EFS at three years was 94% and OS 97%. The difference in EFS between EU and AF is statistically significant (p=0.023) (Figure 1). If eBEACOPP is used for front-line treatment only in patients with high-risk advanced stage disease, this results in paradoxical inversion of EFS between prognostic groups. eBEACOPP should be considered for all newly diagnosed HL patients younger than 60, except those in the lowest risk group.

Recruitment of CD34+cells during large and standard volume apheresis after mobilization with or without plerixafor

Introduction: Chronic lymphocytic leukemia / small lymphocyte lymphoma (CLL) is the most common leukemia among adult Caucasians. It is typically a disease of the elderly, with a median age of onset of 69 years. Clinical course of the disease is variable and the prognosis depends on the clinical stage at the time of diagnosis and other established prognostic factors. Despite the intensive promotion of fludarabin-based protocols as the fundamental treatment of CLL, high dose chlorambucil remains the most efficient monochemotherapy for these patients. Low toxicity, short treatment duration and favorable cost make this therapy a convenient platform for addition of non-toxic targeted drugs, like rituximab. Rituximab is a monoclonal antibody aimed at the CD20-antigen on the surface of B-lymphocytes. Aim: Combination of rituximab and chlorambucil has been in routine clinical use for some time. The aim of this research is to assess its effectiveness. Patients and methods: Twenty- five patients treated at KBC-Zagreb were included in this study. Median age was 67 years. Patients had received high-dose chlorambucil (10-20mg, median 18mg) continuously and 700-800 mg of rituximab. Eight cycels were planned. Treatment was conducted with or without addition of glucocorticoids. In analysis, patients were divided into groups depending on Binet and Rai stages and total tumor mass score as well as other prognostic factors. Adverse events (AE) were evaluated. Assessed outcomes were response rates and survival. Results: Complete remission (CR) was achieved in 12 patients (48%), partial remission (PR) in 7 (28%), 2 patients were refractory to therapy (8%) and in 4 treatment is still ongoing. After median follow-up of 15 months of survivors, progression-free survival (PFS) is 72% and overall survival (OS) 92%. Patients with Binet stage C and Rai stages 3 and 4 have a statistically significant lower PFS than patients with favorable stages (26% vs, 86%, p = 0, 047). The effect of total tumor mass (TTM) score as well as other prognostic factors on PFS was not statistically significant (p > 0, 05). Likewise, correlation between assessed prognostic factors hasn’t been proven. Serious toxicity occurred in 7 patients, 6 of whom were ≥ 65 years. However, correlation between age and toxicity wasn’t statistically significant. The most common serious AE was leukopenia. Conclusion: Combination of rituximab and continuous high- dose chlorambucil is a very effective front- line treatment of CLL, leading to high overall response. Therapy does not cause unexpected toxicity and is well tolerated. To obtain more relevant results for comparison with larger studies, further follow-up and inclusion of new patients is needed.

Prolonged steroid premedication and/or reduction of lymphocyte count with Clb prior to administering first dose of G might result in a lower frequency of severe infusion reactions observed in our series In contrast to rituximab, the combination of G with higher-doses of Clb frequently results in premature stopping of the latter, especially in patients with serious comorbidities. This prevents the delivery of the intended total dose of Clb and reduces the possibility to improve efficacy over G þ Clb pulses.

Evaluation of the clinical utility of the novel heavy/light chain immunoassay for the assessment of multiple myeloma patients.The novel heavy/light chain allows accurate measurement of monoclonal immunoglobulins and can be more sensitive than standard techniques at detecting residual disease. Abnormal heavy/light chain ratios and immunoglobulin isotype pair suppression may have prognostic significance for multiple myeloma patients.