Combination Of Thalidomide Research Articles

Chemotherapy-Induced Peripheral Neuropathy Impacts Quality of Life and Activities of Daily Living of Brazilian Multiple Myeloma Patients.

Survival in multiple myeloma (MM) has improved in the past years with the introduction of immunomodulators and proteasome inhibitors. However, chemotherapyinduced peripheral neuropathy (CIPN) is associated with both drug classes affecting Health- Related Quality of Life (HRQoL) and activities of daily living (ADL). We evaluated CIPN in MM patients to identify associated factors and impacts on HRQoL and ADL. This is a cross-sectional study with Brazilian patients from public and private health services. Patients were interviewed using validated tools to measure CIPN and HRQoL, along with sociodemographic and clinical questions. Logistic regression was used to assess the association of CIPN with sociodemographic, clinical, and HRQoL variables. In total, 217 patients were eligible for the study. The median age was 67, 50.9% were women, 51.6% had low income, 47.5% had low education, and 55.3% attended private health services. The chemotherapy regimen most used was the combination of cyclophosphamide, thalidomide, and dexamethasone (17.5%) among the 24 types of regimens found. Most patients (90.3%) had at least one CIPN symptom: 62.7% were severe, and 51.62% were extremely bothered ADL. Numbness was the most common symptom (40.6%). CIPN was independently associated with education, hospitalization, chemotherapy, side effects, disease symptoms, and global health status in HRQoL. MM patients showed a high frequency of CIPN, which affected ADL and impaired HRQoL. Early and accurate detection of CIPN and dose management in patients with thalidomide and bortezomib-based regimens should be performed to provide better treatment outcomes and avoid permanent disabilities.

Thalidomide and Hydroxyurea in Transfusion-Dependent Thalassemia: Efficacy, Safety Profile and Impact on Quality of Life

Transfusion-dependent thalassemia (TDT) is a major public health concern in India, requiring regular transfusions for survival. There is also significant morbidity caused by iron overload and transfusion related infections. Novel therapies targeting fetal hemoglobin induction are the need of the hour in resource-poor institutions for patients where transplant is not feasible for various reasons. This single arm, non-randomised prospective trial evaluated the efficacy and safety of a combination of low dose thalidomide and hydroxyurea in TDT along with the impact on quality of life (QoL). It included 41 TDT patients, who failed a reasonable trial of hydroxyurea. Complete response (CR) was defined as transfusion independence and partial response (PR) denoted at least a 50% reduction in transfusion requirement. The rest were defined as non-responders (NR). The mean age of the cohort was 20.78 years (range 12–45 years). There were 13 males and 28 females. Nineteen (46.3%), 7 (17.1%), and 15 (36.6%) patients achieved CR, PR, and no response respectively. The overall response rate (CR + PR) was 63.4%. There was a significant increase in hemoglobin levels with decrement in transfusion burden and ferritin levels. There were no significant adverse reactions. No significant predictors of response were found including amongst genetic modifiers. It improved the health related QoL amongst responders. The combination of thalidomide and hydroxyurea appear safe and effective in the reduction in transfusion requirement of TDT patients. The judicious use of these drugs can improve the quality of life and pave the way for patients not eligible for a stem cell transplant.

A Phase 2 Study of Daratumumab in Combination with Thalidomide and Dexamethasone in Relapsed and / or Refractory Myeloma: A Report from the Asian Myeloma Network

Introduction Myeloma is a plasma cell dyscrasia characterised by a relapsing remitting course. Patients with relapsed / refractory myeloma (RRMM) with prior exposure to proteosome inhibitor and an immunomodulatory agent have a poor prognosis. In the last few years, CD38 antibodies such as daratumumab and isatuximab have revolutionised the treatment of multiple myeloma. They appear synergistic with immunomodulatory drugs; triplet combinations with lenalidomide 1 (DRd) or pomalidomide 2 (DPd) and dexamethasone have been approved for treatment of RRMM. However, patients face high out-of-pocket costs when attempting to access these drugs. There is hence a pressing need to develop combinations which harness the therapeutic potential of CD38 antibodies while preserving synergistic action of triplet combinations. Methods This was a multi-national, multi-centre, single arm, phase 2 trial of daratumumab in combination with thalidomide and dexamethasone. Patients with myeloma diagnosed according to the International Myeloma Working Group criteria with measurable disease and relapsing after / refractory to at least one prior line of treatment were eligible for enrolment. Satisfactory organ function (neutrophil count ≥ 1,000/mm 3, platelet ≥ 50,000/mm 3, bilirubin ≤ 1.5 x the upper limit of the normal range (ULN). Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN and creatinine clearance ≥ 30ml/min) were pre-requisites for inclusion. Patients with plasma cell leukaemia and those with prior CD38 antibody exposure were excluded. Patients received daratumumab IV 16mg/kg weekly for weeks 1 - 8, every 2 weeks from weeks 9 - 24 and every 4 weeks from week 25 onwards, thalidomide 100mg daily and dexamethasone 20mg twice a week. Treatment was continued for as long as tolerated and clinically indicated, based on physician assessment, or until disease progression. Thromboprophylaxis was allowed but not mandated. The primary outcome measure was progression-free survival (PFS), defined as the time from commencement of treatment to disease progression or death from any cause, whichever occurred first. Secondary outcome measures included overall response rate (ORR, the percentage of patients achieving a partial response (PR) or better), overall survival (OS), duration of response (DOR, the time from first evidence of PR or better till disease progression or death, whichever occurred first) and safety, assessed by the frequency and severity of adverse events. Results 70 patients were recruited. The median age was 66.8 (range 39 - 81) years with 62.7% males. 95.5% of patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The median number of prior therapies was 2 (range 1 - 6). 91% of patients had prior exposure to bortezomib, while 88% had prior exposure to thalidomide, lenalidomide or both. 50.7% had a prior autologous stem cell transplant. 67 patients completed at least one cycle of treatment. Two died prior to completion of the first cycle, while one withdrew consent and was excluded. Patients were treated for a median of 15.9 (interquartile range, IQR 5.1 - 23) months. 67 (95.7%) patients suffered 544 adverse events, of which 256 (47%) were related to the study treatment, 103 (19%) grades 3-4 and 8 (1%) were fatal. The most common adverse event was infection, which occurred in 26 patients; 4 were fatal. 27 patients had peripheral neuropathy, 25 of which were grade 1 - 2. 14 patients had an infusion reaction, 3 of which required hospitalisation. One patient had a deep vein thrombosis. At a median follow-up of 22.0 (IQR, 9.9 - 31.0) months, the median PFS was 16.3 (95% CI, 12.8 - 24.6) months (Figure 1). The median OS was 32.5 (95% CI, 25.4 - not reached) months. The ORR was 82.1% (95% CI, 70.8 - 90.4). This ORR was comparable to DRd and DPd (Table 2). Of these, 43 (78%) of patients achieved a very good partial response (VGPR) or better, with 9 (16%) of patients achieving a stringent complete response (sCR). The median DOR was 19.3 (95% CI, 12.2 - 36.5) months. Conclusion The combination of daratumumab, thalidomide and dexamethasone is effective in RRMM patients. Thalidomide and dexamethasone are cost-effective drugs which can improve the accessibility of daratumumab-based triplet combinations.

Maintenance therapy with a combination of azacitidine, danazol, and thalidomide after intensive chemotherapy in patients with acute myeloid leukemia

ABSTRACTObjectiveThis study aimed to evaluate the efficacy of azacitidine (AZA) combined with danazol (DNZ) and thalidomide (THD) maintenance therapy after intensive chemotherapy (IC) in patients with acute myeloid leukemia (AML).Methodswe retrospectively analyzed the clinical data of 11 patients treated with AZA combined with DNZ and THD as maintenance therapy after IC at the Baiyun Hospital were between February 2017 and March 2021. The patients' clinical features, relapse-free survival (RFS), and overall survival (OS) were analyzed.ResultsEleven cases fulfilled the AML criteria per the 2016 World Health Organization classification. Of the 11 patients, five were females, and six were males, with a median age of 45 years (range, 23-65 years). Ten patients were in the first complete remission (CR1), and one patient was in the second complete remission (CR2). All patients received AZA combined with DNZ and THD maintenance therapy after IC. The median number of AZA cycles received was 7 (6-12). Until June 2022, the median follow-up period was 37 (14-63) months; one patient had a relapse, and three died. RFS at 1 year and 3 years was 100% and 71.1%, respectively, and OS at 3 years was 100%.ConclusionAZA combined with DNZ and THD maintenance therapy is effective for patients with AML who are ineligible for allogeneic hematopoietic stem cell transplantation. Further studies with large sample sizes and randomized are needed to verify these findings.

The Impact of Epstein-Barr Virus Infection on Second Cancer Development in Newly Diagnosed Myeloma Patients Treated with Lenalidomide in the UK NCRI Myeloma XI Trial

Background Several factors have been linked to second primary malignancy (SPM) development in myeloma patients, including advanced age, immunocompromise and therapy, such as melphalan and lenalidomide (len). The impact of infection, including EBV is yet to be elucidated. Here we address this in the context of the UK NCRI Myeloma XI Trial for newly diagnosed transplant eligible (TE) and transplant non-eligible (TNE) patients. Methods Myeloma XI was a phase III, randomised, multi-centre, parallel group design, open-label trial comparing cyclophosphamide, thalidomide, len, carfilzomib and bortezomib induction combinations and len maintenance treatment in TE and TNE patients. TE patients received high dose melphalan supported by autologous stem cell transplantation (ASCT). Patients in both pathways were randomised to maintenance with len or observation. In total, 4358 patients entered. Planned SPM analysis was conducted in May 2019, with 318 patients developing an SPM prior to that point. Median follow-up from trial entry was 60 months (IQ range 47-76). A nested cohort analysis was performed to determine EBV infection and immunity status in 170 SPM patients for which serum samples were available. Forty-two trial patients who did not develop an SPM were used as a control group. EBV assessment time-points included pre-induction, post induction, 4 months post ASCT (TE only) and 1 year post induction. Peripheral blood serum samples were tested for EBV EBNA IgG Antibody/index (LIAISON®), EBV VCA IgM Antibody/Index (LIAISON®) and EBV positivity was determined using the artus® EBV RG PCR Kit from Qiagen. Active or recent EBV infection was evidenced by a positive EBV IgM antibody and/or EBV PCR. Results Of the 170 patients, 208 SPM were noted with 147 patients developing 1 SPM and 23 patients developing ≥2. One hundred and five patients developed an SPM following maintenance randomisation, with 76 receiving len and 29 being observed. The remaining 65 patients developed an SPM prior to maintenance. Eighty-four SPMs were diagnosed in 68 TE patients and 124 SPMs in 102 TNE patients. Of the 170 SPM patients, 8 had evidence of recent or active infection at the time of testing, evidenced by either IgM EBV antibodies (n=5), positive EBV PCR (n=2) or both (n=1). The median EBV DNA copies/ml was 353 (range 337-428). The median IgM antibody titre was 71.5U/ml (26 - >160). No patients in the control group had evidence of recent EBV infection (p=0.36). Of the 8 patients with evidence of EBV infection, 6 developed >1 SPM, Table 1. Five had been treated in the TE pathway, with all developing post maintenance randomisation, and 4 of the 5 receiving len maintenance. None of the 3 TNE patients received len maintenance, with 2 developing an SPM prior to maintenance randomisation. The median time from EBV testing to SPM diagnosis was 17·9 months (0.5-51.7). Two of the EBV positive patients developed a haematological SPM: myelodysplastic syndrome and Hodgkin lymphoma. Four patients developed a solid malignancy: lung, breast, ovary, and colon. The remaining cases were non-melanoma skin cancers, Table 1. Immune status (EBV IgG) was also determined. In TE patients, the median EBV IgG titre was 65.3U/ml at diagnosis (<3 - 600, n=48), falling to 28.1U/ml following induction (<3 - 326, n=41) and recovering to 44.2U/ml one year post ASCT (<3 - 600, n=22). In TNE patients, the median IgG titre at diagnosis was 39.1U/ml (<3 to 517, n=72), falling to 31.2U/ml 4 months post induction (<3 - 287, n=42) and recovering to 51.3U/ml after 1 year (<3 - 554, n=41). In the SPM patients the IgG EBV titres were noted to be <20U/ml in 5 of the 8 patients. Three of the eight patients had no detectable EBV IgG level (<3U/ml) Conclusions These data suggest that EBV infection is unlikely to be a risk factor for SPM development in myeloma patients. This is supported by the finding that EBV IgG titres were consistent with immunity in most patients (>20U/ml) and even in the patients with possible EBV infection, EBV DNA was only identified in 3 patients, and at a low level. In addition, the SPM developed are not classically associated with EBV infection or reactivation. It is noted that EBV infection status was not always determined at the time of SPM development. Despite this, the data does show that EBV immunity recovers following therapy, even in the post ASCT setting. EBV monitoring is therefore not supported by this work, although in patients who develop ≥2 SPM, further clarification is required.

Cause analysis of conversion to biologics in spondyloarthritis patients with poor response to conventional treatment.

We sought to investigate the reasons why spondyloarthritis (SpA) patients failed to respond to non-steroidal anti-inflammatory drugs (NSAIDs) and conventional synthetic disease-modifying antirheumatic drugs (cDMARDs) and the influences of different initial cDMARDs on the likelihood of a switch to biologics. SpA patients were divided into a conventional drug maintenance group and a biologics conversion group to determine the causes of conversion to biologics. Then, we divided all patients into three groups according to different initial cDMARDs, NSAID monotherapy, NSAID + (sulfasalazine or thalidomide) double combination, and NSAID + sulfasalazine + thalidomide triple combination therapy groups, to clarify the influence of initial treatment on later conversion to biologics. This study includes 202 patients, including 97 patients in the conventional drug maintenance group and 105 patients in the biologics conversion group. The mean age of the conventional drug maintenance group was higher than that of the biologics conversion group (40.8 ± 14.3 vs. 33.8 ± 12.3 years, P < 0.05). Uveitis (OR 5.356, P < 0.05) is positively correlated with conversion to biological therapy, while age (OR 0.940, P < 0.05) is negatively correlated. The proportion of NSAID monotherapy, double combination, and triple combination groups converted to biological agents was 80%, 51.1%, and 23.2%, respectively (P < 0.05). Age and uveitis are related to conversion to biologics therapy. The early combination of sulfasalazine and thalidomide with NSAIDs may lower the probability of conversion to biologics therapy in the later stage and offer a new option for patients with limited use of biologics in SpA patients. Key Points • Patients' move to biologics may be caused mostly by inadequate disease control by conventional oral medications. • Regardless of axial vs. peripheral joint involvement, combination drug therapy was superior to single drug therapy in controlling SpA and decreasing the probability of conversion to a biological agent. • For SpA patients who are not candidates for biologics due to contraindications or other reasons, early combination application of NSAIDs, sulfasalazine, and thalidomide may be a new choice.

Haploinsufficiency of A20 caused by a novel pathogenic missense variant of TNFAIP3 and successfully treated with anti-TNF and immunosuppressive therapies

Loss-of-function of protein A20, encoded by TNFAIP3, leads to an early-onset haploinsufficiency of A20 (HA20). This study reports one Chinese child with HA20 and explores the genetic etiology of TNFAIP3 variant. The patient exhibited transient recurrent episodes of fever, intermittent signs of arthritis, gastrointestinal symptoms and multiple colonic ulcers. Laboratory tests revealed elevated inflammatory indicators and mild to moderate anemia. Genetic analysis identified a heterozygous de novo variant in his TNFAIP3 gene (c.740C＞T, p. P247L), which had never been reported before. The novel missense variation was validated to be pathogenic through causing insufficient expression of A20, over-activation of NF-κB signaling pathway and elevated levels of proinflammatory cytokines in response to stimulation by lipopolysaccharide. A combination of oral corticosteroids, TNF-α inhibitors and thalidomide freed him from symptoms and abnormal inflammatory indicators. Furthermore, continual improvement of the patient's condition was observed during a follow-up period of five months. We demonstrate a case with a de novo missense variant resulting in a loss-of-function of TNFAIP3, which expands the clinical spectrum of HA20. Cytokine antagonists and immunosuppressants may be effective drugs.

Combination of thalidomide and Clostridium butyricum relieves chemotherapy-induced nausea and vomiting via gut microbiota and vagus nerve activity modulation.

Nausea and vomiting (CINV) are distressful and widespread side effects of chemotherapy, and additional efficient regimens to alleviate CINV are urgently needed. In the present study, colorectal cancer (CRC) mice model induced by Azoxymethane (AOM)/Dextran Sodium Sulfate (DSS) was employed to evaluate the cancer suppression and CINV amelioration effect of the combination of thalidomide (THD) and Clostridium butyricum. Our results suggested that the combination of THD and C. butyricum abundantly enhanced the anticancer effect of cisplatin via activating the caspase-3 apoptosis pathway, and also ameliorated CINV via inhibiting the neurotransmitter (e.g., 5-HT and tachykinin 1) and its receptor (e.g., 5-HT3R and NK-1R) in brain and colon. Additionally, the combination of THD and C. butyricum reversed the gut dysbacteriosis in CRC mice by increasing the abundance of Clostridium, Lactobacillus, Bifidobacterium, and Ruminococcus at the genus level, and also led to increased expression of occludin and Trek1 in the colon, while decreased expression of TLR4, MyD88, NF-κB, and HDAC1, as well as the mRNA level of IL-6, IL-1β, and TNF-α. In all, these results suggest that the combination of THD and C. butyricum had good efficacy in enhancing cancer treatments and ameliorating CINV, which thus provides a more effective strategy for the treatment of CRC.

Therapeutic effects of thalidomide on patients with systemic sclerosis-associated interstitial lung disease.

To evaluate the clinical efficacy of thalidomide in patients with systemic sclerosis-associated interstitial lung disease. Ninety-six systemic sclerosis-associated interstitial lung disease patients who received basic glucocorticoid treatment and admitted between 2016 and 2020 were included in this study, including 48 cases in the thalidomide group (combination of thalidomide and cyclophosphamide) and 48 cases in control group (cyclophosphamide monotherapy). Evaluation items included clinical symptoms, modified Rodnan skin score, pulmonary function test, chest high-resolution computed tomography scores, and adverse effects between two groups after 24 weeks of treatment. Remarkable improvements in several aspects were found in the thalidomide group, including modified Rodnan skin score, expiratory dyspnea score, cough visual analog scale score, total ground-glass opacity score, and total interstitial lung disease score. Compared to the control group, improvements in the thalidomide group were found, such as significantly decreased cough visual analog scale score and expectoration; increased number of platelets; improved pulmonary fibrosis (p = 0.056), and reduced carbon monoxide diffusing capacity (p = 0.053). There were no statistically significant differences in the expiratory dyspnea score and predicted forced vital capacity between the two groups. Patients who experienced at least one adverse event in the control group and thalidomide group were 33.3% and 64.6% (p = 0.002); while those with serious adverse events were 8.3% versus 12.5% (p = 0.504). Venous thrombosis was found in one case in the thalidomide group. Thalidomide combined with cyclophosphamide can improve the symptoms of cough and expectoration in patients with systemic sclerosis-associated interstitial lung disease, and may slightly delay the progression of pulmonary fibrosis, but with the possibility of an increased risk of adverse events.

Potential Use of Thalidomide in Glioblastoma Treatment: An Updated Brief Overview.

Glioblastoma is the most common malignant primary brain tumor in adults. Thalidomide is a vascular endothelial growth factor inhibitor that demonstrates antiangiogenic activity, and may provide additive or synergistic anti-tumor effects when co-administered with other antiangiogenic medications. This study is a comprehensive review that highlights the potential benefits of using thalidomide, in combination with other medications, to treat glioblastoma and its associated inflammatory conditions. Additionally, the review examines the mechanism of action of thalidomide in different types of tumors, which may be beneficial in treating glioblastoma. To our knowledge, a similar study has not been conducted. We found that thalidomide, when used in combination with other medications, has been shown to produce better outcomes in several conditions or symptoms, such as myelodysplastic syndromes, multiple myeloma, Crohn's disease, colorectal cancer, renal failure carcinoma, breast cancer, glioblastoma, and hepatocellular carcinoma. However, challenges may persist for newly diagnosed or previously treated patients, with moderate side effects being reported, particularly with the various mechanisms of action observed for thalidomide. Therefore, thalidomide, used alone, may not receive significant attention for use in treating glioblastoma in the future. Conducting further research by replicating current studies that show improved outcomes when thalidomide is combined with other medications, using larger sample sizes, different demographic groups and ethnicities, and implementing enhanced therapeutic protocol management, may benefit these patients. A meta-analysis of the combinations of thalidomide with other medications in treating glioblastoma is also needed to investigate its potential benefits further.

The Effects of Multi-Donor Fecal Microbiota Transplantation Capsules Combined with Thalidomide on Hormone-Dependent Ulcerative Colitis.

This study aimed to assess the effects of multi-donor fecal microbiota transplantation (FMT) capsules combined with thalidomide on hormone-dependent ulcerative colitis (UC). A total of 59 patients with steroid-dependent UC treated at the Gastroenterology Department of the First Affiliated Hospital of Xinxiang Medical University between January 2017 and January 2019 were enrolled in this study. Using a random number table, the patients were divided into two groups: a group treated with FMT capsules (the FMT group) and a group treated with FMT capsules and thalidomide (the FMT+S group). Multi-donor FMT capsules were prepared, and all subjects and stool donors followed the FMT pathway for FMT transplantation. Each patient's Mayo score, C-reactive protein (CRP) level, and level of fecal calprotectin before FMT treatment and at week 1 and week 13 after treatment were recorded. All patients were followed up for 15 weeks. A total of 56.7% of the patients (34/59) achieved a therapeutic response at the end of the research period. Compared with the FMT group, the FMT+S group had better clinical benefit (P < 0.05). In the comparison of efficacy at week 1 and week 13 after treatment, the Mayo scores, calprotectin levels, and CRP indexes in the FMT+S group were better than those in the FMT group (P < 0.05). There were no serious adverse events in the treatment process or during follow-up. A combination of FMT capsules and thalidomide provides a treatment choice for patients with hormone-dependent UC, and it can be used as an adjuvant therapy. However, large-scale, multi-center, and prospective trials are required to further verify the reliability of this treatment.

Maintenance Therapy with Combination of Azacitidine, Danazol and Thalidomide after Intensive Chemotherapy in Acute Myeloid Leukemia Patients

INTRODUCTION Despite the efficacy and outcome of AML patients increases in recent decades, the rate of relapse is still high, especially in the patients who are ineligible for allo-HSCT. How to prevent relapse is still a major therapeutic challenge. Recently, several drugs including Azacitidine (AZA), CC-486, Lenalidomide, androgen, Midostaurin, etc, used as maintenance therapy have shown a better EFS or OS, indicating that maintenance therapy is an important aspect of AML treatment. Herein, we reported the data of 11 AML patients who were administered AZA combined with Danazol (DNZ) and Thalidomide (THD) as maintenance therapy after intensive chemotherapy (IC). The purpose of this study was to observe the efficacy and safety of this maintenance therapy. METHODS Between Feb 2017 and Mar 2021, 11 patients diagnosed with AML were treated at the Baiyun Hospital. The induction therapy involved daunorubicin (DNR) 60 mg/m2/day on days 1-3, cytarabine (Ara-c) 100 mg/m2/day on days 1-7. If the patient did not achieve CR, salvage therapy was administered. Post-remission, three cycles of consolidation chemotherapy with high-dose Ara-c (3g/m2/q12h d1-3) and two cycles of reduced dose of chemotherapy (DA/HA/EA) were administered. Patient remained in CR after IC and was treated with 6-8 cycles of AZA combined with DNZ and THD maintenance therapy. AZA subcutaneous injection at 100 mg/day (approximate 50-75 mg/m2/day) d1-7, DNZ 200 mg Bid and THD 100 mg/day po followed by AZA, every four weeks. After completing the 6-8 cycles, patients continued the maintenance therapy with DNZ and THD for at least three years unless relapse or intolerance occurred. Disease evaluation included bone marrow and blood test until the duration of CR over five years. RESULTS Between Feb 2017 and Mar 2021, 11 patients who were enrolled in this study. Baseline patient and disease characteristics are summarized in Table 1. All 11 patients were treated with DA induction therapy, 10 patients achieved CR, 1 patient achieved remission after salvage therapy. 10 of 11 patients completed all consolidation therapies. 1 patient diagnosed AML with t (8;21) refused to continue chemotherapy because of renal failure after CR, and was directly switched to maintenance therapy. 9 0f 10 patients completed all IC and started on maintenance therapy. 1 AML with t (8;21) patient relapsed after stopping chemotherapy for two months and achieved CR2 by FLAG re-induction therapy refused continued chemotherapy and transplantation, and was directly switched to maintenance therapy. All patients received a median of 7 (6-12) courses of AZA combined with DNZ and THD maintenance therapy. Treatment was well tolerated and accepted by the patients. Common adverse events included mild neutropenia, thrombocytopenia, and elevated aminotransferase. No patient discontinued the maintenance therapy due to adverse events. Until June 2022, the median follow-up time was 37 (14-63) months. The RFS at 1-year and 3-years was 100% and 71.1%; the OS at 3-years was 100%, respectively (Figure 1a, 1b). All 11 patients, 3 died and 8 patients were alive with RFS. Of the 3 patients who died, 1 relapsed at 36 months and died due to disease progression at 46 months. The remaining 2 patients, one was diagnosed and died with secondary mixed phenotypic acute leukemia (NOS, T/My), the other died in a road accident. Notably, 2 cases of AML with t (8; 21) (one patient relapsed after IC, another patient developed renal failure) remained in CR by the end of follow-up. The CR duration was 24 and 13 months, respectively. The clinical outcomes of maintenance therapy after IC treatment for 11 patients are summarized in Figure 1c. Conclusion: AZA combined with DNZ and THD maintenance therapy is safe and effective in AML patients who are ineligible for allo-HSCT. Keywords: Azacitidine; Danazol; thalidomide; maintenance therapy; AML Figure 1 Response and long-term outcomes of the entire cohort Figure 1 legend, a. Relapse-free survival of the 11 patients. b. Overall survival of the 11 patients. c. Swimmer plot of the 11 patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Second Primary Malignancy Incidence in Patients Receiving Lenalidomide at Induction and Maintenance; Long-Term Follow up of 4358 Patients Enrolled to the Myeloma XI Trial

Background Early trials of long-term lenalidomide (len) use reported an increased incidence of second primary malignancies (SPM), including acute myeloid leukaemia and myelodysplastic syndrome. Later, meta-analysis suggested the link to be secondary to len in combination with melphalan. Here we address the impact of len on SPM development when used at induction and maintenance, profiling SPM type and incidence in 4358 patients treated in the UK NCRI Myeloma XI trial, in which len was used at induction and maintenance, in transplant eligible (TE) and non-eligible (TNE) newly diagnosed patients. Methods Myeloma XI was a phase III, randomised, multi-centre, parallel group design, open-label trial comparing cyclophosphamide, thalidomide, len, carfilzomib and bortezomib induction combinations and len as maintenance treatment in newly diagnosed patients. TE patients received high dose melphalan supported by autologous stem cell transplantation. Patients in both pathways were randomised to maintenance with len (+/- vorinostat) or active observation. Within the TE pathway, 701 patients did not receive len at induction or maintenance, 1263 received len at induction or maintenance (single exposure) and 568 received len at induction and maintenance (double exposure). In TNE patients, 677 were not treated with len, 899 were single exposed and 260 double exposed. Median follow-up was 68 months (IQ range 49-83). Results 138 TE patients (IR 5.5%) developed an SPM, with 85 diagnosed following maintenance randomization (IR 5.9%). TE patients receiving len maintenance had an SPM incidence of 12.2% at 7 years, compared to 5.8% in those being observed (Pepe-Mori p=0.003). When profiling the SPM type, the incidence of most cancers was greater in the double exposed patients (non-exposed IR 1.6%, single exposed IR 2.9%, double exposed IR 8.3%). Despite this, the actual incidence was <1% for each SPM type in all groups, except for BCC (1.4%), SCC (1.2%) and MDS (1.1%) noted in >1% of double exposed patients. Haematological SPM were almost all confined to the len treated patients, with most in the double exposed group, Figure 1a. 180 TNE patients (IR 9.9%) developed an SPM, with 110 diagnosed following maintenance randomization (IR 13.2%). TNE patients receiving len maintenance had an SPM incidence of 17.1% at 5 years, compared to 10% in those being observed (p=0.09). There was a greater incidence of most SPM types in the double exposed patients (non-exposed IR 2.8%, single exposed IR 6.7%, double exposed IR 18.1%). Skin cancers were common, particularly in the double exposed patients, with an SCC incidence of 4.6% and BCC incidence of 3.1%. No SPM type was diagnosed in >1% of patients who did not receive len. In the double exposed patients, prostate cancer (1.2%) and melanoma (1.2%) were also noted in >1% of patients, Figure 1b. Haematological SPM were rare in TNE patients, with only 8 patients diagnosed, 7 of whom received len. We also determined the outcome in patients treated with len maintenance. In TE patients, 13 (IR 1.8%) deaths were secondary to an SPM, compared to 121 (IR 16.6%) myeloma related and 18 (IR 2.5%) non-myeloma related deaths. This compared to 2 (IR 0.4%) SPM deaths, 117 (IR 22.6%) myeloma related and 19 (IR 3.7%) non-myeloma related deaths in the observed patients. In TNE len maintenance patients, 25 (IR 6.1%) died due to a SPM, 133 (32.7%) due to progressive myeloma and 44 (IR 10.8%) due to other causes. In the observed TNE patients, 9 (IR 2.8%) died due to an SPM, 131 (IR 41.5%) due to progressive myeloma and 28 (IR 8.9%) secondary to non-myeloma related issues. Conclusions SPM incidence was higher in patients treated with len at both induction and maintenance compared to single exposure or no exposure. This was most marked in the TNE patients suggesting an innate risk of SPM development in older patients, particularly skin cancers, possibly impacted by len. Focusing on the maintenance therapy, there was a significant increase in SPM incidence in TE patients treated with len maintenance compared to observation. In TNE patients there was also a numerical increase in SPM incidence that did not reach statistical significance. Deaths due to SPM were rare but increased with lenalidomide maintenance. However, deaths due to myeloma were lower in patients treated with len. We suggest that clinic review of patients receiving maintenance len should include a history focused on identifying possible SPM, so intervention can be made early. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Daratumumab (Dara), Cyclophosphamide, Thalidomide and Dexamethasone for Transplant Eligible Newly Diagnosed Multiple Myeloma (TE NDMM) Patients: Response Rate Impacts on PFS

Background: The introduction of monoclonal antibodies (mAb) such as daratumumab created a new landscape for MM treatment. The four-drug combo has becoming one of the main induction treatment for TE NDMM patients (pts). We conducted a phase 2 study to assess the safety and preliminary efficacy of Cyclophosphamide (C), thalidomide (T), dexamethasone (d)-(CTd) and Dara combination. MAXDARA study has shown in the primary analysis with 21 included patients (pts), 4 and 8 pts MRD negativity after four induction cycles and two consolidation cycles post transplant, respectively. (Crusoe E et al ASH 2020, 2416 poster presentation). In the present analysis we evaluate the effect of deep response rate on PFS. Primary endpoint of the study was to evaluate the VGPR after two consolidation cycles post-autologous stem cell transplantation (ASCT). Methods: This is a phase II, open-label single-center clinical trial. The main inclusion criteria were: TE NDMM, creatinine clearance > 30 ml/min, normal cardiac, renal and liver function and the Easter Cooperative Oncology Group (ECOG) performance status = 0 - 2. The protocol was Dara-CTd for up to four 28-day induction cycles: C-500mg oral (PO) on days 1,8 and 15, T at 100-200mg PO on days 1 to 28, (d) at 40mg PO on days 1,8,15 and 22 and Dara at 16mg/Kg/dose intravenous (IV) on days 1,8,15 and 22 during cycles 1 - 2 and every other week in cycles 3 - 4, followed by ASCT. All pts received up to four 28-day consolidation cycles that was started at D+30 after ASCT: Dara at 16mg/Kg and (d) at 40mg every other week, associated with T at 100mg PO on days 1 - 28. Dara at 16mg/Kg was used monthly as maintenance until progression or limiting toxicity. The MRD was evaluated by next-generation flow (NGF) 10-6 and PET-CT was performed when the patient obtained NGF negativity or finished consolidation. PFS outcome was estimated using Kaplan-Meier method and PFS analysis were performed based on the different response rates. ( Data cut-off was April 2022) Results: A total of 24 pts were included. The median age being 58 (range 37- 67 years), 15 (62.5%) pts were female, 23 (92%) were non-white, 6 (25%) had an R-ISS = 1, 12 (50%) had an R-ISS = 2 and 4 (16%), an R-ISS = 3. Sixteen (66.7%) pts were IgG isotype and Six (25%) had high-risk chromosomal abnormalities [1q+, del17p, t(4;14) or t(14;16)]. To date, 23 pts have completed induction, 21 performed transplant and 14 are still in treatment after one year of dara maintenance. No stem cell mobilization failure was observed, and six (30%) pts needed plerixafor use. By ITT analysis, 22 pts (91.6%) achieved (> PR) after 4 induction cycles. One pts achieved SD, one MR and one sCR. Eleven (39%) pts achieved PR, and 10 (35.7%) VGPR. After two consolidation cycles, ORR was 68%, 8 (28.6%) and 11 (39.3%) pts obtained sCR and VGPR, respectively. The best response during any time of the treatment were PR in 3 (12.5%) pts, VGPR in 12 pts (50%) and sCR in 8 (33.3%) pts. In a ITT analysis, NGF MRD 10-6 negativity were observed in 4(16.6%) after four induction cycles, and in 17 (70.8%) pts after two consolidation cycles post-ASCT. In a ITT analysis, after a median follow up (FU) of 26 months, the PFS was 37months for the entire group. The median PFS comparing sCR vs < VGPR were 37m vs 27m (p=0.021), respectively, and comparing MRD negative by NGF vs no, had impacted even more on PFS with a median of 37m vs 16m (p=0.004), respectively. The OS was not yet achieved and 83% of the patients still alive after a median FU of 27 months. Four pts died from infection, two of them related with covid infection (one before transplant and one during maintenance). Another case post-transplant, considered not related to the investigational agent and one after consolidation, related to the investigational agent. Summary/Conclusion: The Daratumumab - CTd protocol is an active and safe regimen capable of producing deep and sustainable responses. The deeper response rate impacted on PFS, confirm that MRD negativity is critical to patient outcome. Clinical trial information: NCT03792620.

DARATUMUMAB (DARA), CYCLOPHOSPHAMIDE, THALIDOMIDE AND DEXAMETHASONE FOR TRANSPLANT ELIGIBLE NEWLY DIAGNOSED MULTIPLE MYELOMA (TE NDMM) PATIENTS: RESPONSE RATE IMPACTS ON PFS

The four-drug combo has becoming one of the main induction treatment for TE NDMM patients (pts). We conducted a phase 2 study to assess the safety and preliminary efficacy of Cyclophosphamide (C), thalidomide (T), dexamethasone (d)-(CTd) and Dara combination. MAXDARA study has shown in the primary analysis with 21 included patients (pts), 4 and 8 pts MRD negativity after four induction cycles and two consolidation cycles post transplant, respectively. (Crusoe E et al ASH 2020, 2416 poster presentation). In the present analysis we evaluate the effect of deep response rate on PFS. This is a phase II, open-label single-center clinical trial. The main inclusion criteria were: TE NDMM, creatinine clearance > 30 ml/min, normal cardiac, renal and liver function and the ECOG performance status = 0 - 2. The protocol was Dara-CTd for up to four 28-day induction cycles: C-500mg oral (PO) on days 1,8 and 15, T at 100-200mg PO on days 1 to 28, (d) at 40mg PO on days 1,8,15 and 22 and Dara at 16mg/Kg/dose intravenous (IV) on days 1,8,15 and 22 during cycles 1 - 2 and every other week in cycles 3 – 4, followed by ASCT. All pts received up to four 28-day consolidation cycles that was started at D+30 after ASCT: Dara at 16mg/Kg and (d) at 40mg every other week, associated with T at 100mg PO on days 1 - 28. Dara at 16mg/Kg was used monthly as maintenance until progression or limiting toxicity. The MRD was evaluated by next-generation flow (NGF) 10−6 and PET-CT was performed when the patient obtained NGF negativity or finished consolidation. PFS outcome was estimated using Kaplan–Meier method and PFS analysis were performed based on the different response rates. (Data cut-off was April 2022) A total of 24 pts were included. The median age being 58 (range 37– 67 years), 15 (62.5%) pts were female, 22 (92%) were non-white, 6 (25%) had an R-ISS = 1, 12 (50%) had an R-ISS = 2 and 4 (16%), an R-ISS = 3. Sixteen (66.7%) pts were IgG isotype and Six (25%) had high-risk chromosomal abnormalities [1q+, del17p, t(4;14) or t(14;16)]. To date, 23 pts have completed induction, 21 performed transplant and 14 are still in treatment after one year of dara maintenance. By ITT analysis, 22 pts (91.6%) achieved ( > PR) after 4 induction cycles. One pts achieved SD, one MR and one sCR. Eleven (39%) pts achieved PR, and 10 (35.7%) VGPR. After two consolidation cycles, ORR was 68%, 8 (28.6%) and 11 (39.3%) pts obtained sCR and VGPR, respectively. The best response during any time of the treatment were PR in 3 (12.5%) pts, VGPR in 12 pts (50%) and sCR in 8 (33.3%) pts. In a ITT analysis, NGF MRD 10−6 negativity were observed in 4(16.6%) after four induction cycles, and in 17 (70.8%) pts after two consolidation cycles post-ASCT. In a ITT analysis, after a median follow up (FU) of 26 months, the PFS was 37months for the entire group. The median PFS comparing sCR vs < VGPR were 37m vs 27m (p = 0.021), respectively, and comparing MRD negative by NGF vs no, had impacted even more on PFS with a median of 37m vs 16m (p = 0.004), respectively. The OS was not yet achieved and 83% of the patients still alive after a median FU of 27m. Four pts died from infection, two of them related with covid infection (one before transplant and one during maintenance). Another case post-transplant, considered not related to the investigational agent and one after consolidation, related to the investigational agent. The Daratumumab - CTd protocol is an active and safe regimen capable of producing deep and sustainable responses. The deeper response rate impacted on PFS, confirm that MRD negativity is critical to patient outcome.

Response and Survival Estimates of Patients With Plasma Cell Myeloma in a Resource-Constrained Setting Using Protocols From High-Income Countries: A Single-Center Experience From Sri Lanka.

PURPOSEThere is a significant disparity in global cancer care and outcome between countries. Progress in the treatment of symptomatic plasma cell myeloma (PCM) in high-income countries is not seen in low- and middle-income countries.MATERIALS AND METHODSThis is was a retrospective cohort study of all patients diagnosed with PCM between May 1, 2013, and September 30, 2021, at the first hemato-oncology center in Sri Lanka. We aimed to provide data on clinicopathologic characteristics, response, and survival estimates.RESULTSA total of 79 patients with PCM received first-line therapy during the study period. The median age was 64 years, and approximately one third (33%) of patients were older than 70 years. There were 42 (53%) males and 37 females. Hypercalcemia, renal impairment, anemia, and bone disease were detected in 36.7%, 38%, 72.1%, and 81%, respectively. Thirty-nine, 34, and six patients received a combination of cyclophosphamide, thalidomide, and dexamethasone; bortezomib, thalidomide, and dexamethasone; and other treatments, respectively. The overall response rate (≥ partial response) was approximately 97% for both cyclophosphamide, thalidomide, and dexamethasone and bortezomib, thalidomide, and dexamethasone. Twenty-three (29%) of these patients died during the study period, but only 14 (18%) died due to PCM or associated sepsis. After a median follow-up of 40.6 months (range, 35.2-59.07 months), the median overall survival was 84.2 months (95% CI, 60.87 to not available). The 5-year estimated overall survival was 65%.CONCLUSIONTo our knowledge, this is the only well-characterized study on long-term survival of patients with PCM in Sri Lanka. We have shown that it is possible to successfully apply Western treatment and supportive care protocols to the local population. These published data will help to benchmark and improve the treatment and develop blood cancer care in the local setting.

Evaluation of the combination therapy of hydroxyurea and thalidomide in β-thalassemia

AbstractTransfusion-related complications and lack of resources in low-to-middle-income countries have led to a search for novel therapies to reduce the need for blood transfusions in patients with β-thalassemia. Hydroxyurea (HU) has demonstrated promising outcomes; additionally, thalidomide has also shown improvement in hemoglobin (Hb) levels for patients with β-thalassemia in some studies. This study presents the findings of a single-arm nonrandomized trial to evaluate the efficacy of combination therapy of HU and thalidomide in children with β-thalassemia. A total of 135 patients (median age, 6 [interquartile range, 3-10] years), 77 (57%) males and 58 (43%) females, were followed first using HU alone, for 6 months, and then using the combination of HU and thalidomide for another 6 months. The primary outcome was a response to therapy, as measured by the number of transfusions required and Hb levels, for patients while receiving HU alone and then while using the combination therapy. Study findings showed a significant decline in blood transfusion volume (P < .001) and a significant increase in median Hb levels within 3 and 6 months of the combination therapy (P < .001). Eighty-nine (65.93%) participants were good responders, 16 (11.85%) were responders, and 30 (22.22%) were nonresponders, whereas the responders had variable genetic mutations. A total of 38 adverse events were reported that resolved on supportive treatment or temporary hold of the intervention. The combination therapy demonstrated promising results and could be considered for a diverse patient population with β-thalassemia. This trial was registered at www.clinicaltrials.gov as #NCT05132270.

Safety and Efficacy of Thalidomide and Hydroxyurea Combination in Beta Thalassemia Patients.

Beta thalassemia results from imbalance in alpha and beta globin chains causing severe anemia, transfusion dependency, and iron overload. Hematopoietic stem cell transplantation (HSCT) is the only curative treatment. Patients without the option of HSCT may benefit from Hemoglobin F (HbF) inducing agents like thalidomide and hydroxyurea (HU). We conducted a retrospective analysis on 87 beta thalassemia patients who received a combination of low dose thalidomide and HU from January 2017 to December 2020. Patients received combination of HU 500mg everyday (> 30kg) or every alternate day (< 30kg) and thalidomide 100mg (> 30kg) or 50mg (< 30kg) once daily. Parameters such as transfusion requirement, anthropometry, Hb levels, ferritin, drug side effects etc. were monitored and evaluated at the end of one year of therapy. Sixty-three patients (72%) achieved transfusion independence and were eligible for the study. Median time to transfusion independence was 6months (range 3-11months). At the end of 1year, overall response rate was 72%. There was significant improvement in the Hb levels, ferritin values and height at the end of 1year of follow up. No grade 3 or 4 toxicities were noted. We document improvement of Hb levels, transfusion independence, reduction in iron overload, and improvement in growth parameters with minimal side effects at the end of 1year of follow up.

Endoskopická a lékařská terapie žaludeční antrální vaskulární ektázie: případová řada a přehled dostupných metod

Gastric antral vascular ectasia (GAVE) is an uncommon dia­gnosis leading to chronic iron deficiency anaemia caused by occult or overt gastrointestinal bleeding. The mainstay of the therapy is based on endoscopic therapy using endoscopic thermal methods – particularly argon plasma coagulation and others – radiofrequency ablation, coagulation or cryotherapy. Endoscopic band ligation presents satisfying results as well. Pharmacotherapy aiming at reduction of the development of new vascular lesions and reduction of blood flow in them could be considered in patients refractory to endoscopic treatment. We present a review of available endoscopic and non-endoscopic methods for GAVE therapy and our experience with the therapy of refractory GAVE using a combination of endoscopic methods and thalidomide on case series. The algorithm for GAVE therapy is proposed.

Inferior Clinical Outcomes with Fixed Duration Therapy for Transplant Ineligible Myeloma Patients: UK Real-World Data in Comparison with First Trial (MM-020)

BACKGROUNDContinuous therapy for patients with transplant-ineligible (TNE) newly diagnosed multiple myeloma (NDMM) is an emerging treatment concept, based on the results of the FIRST trial (MM-020). In the United Kingdom, the current standard of care for patients with TNE NDMM is based on fixed-duration therapy (FDT) for the first 2 lines, primarily consisting of 6-8 cycles of either a bortezomib (BOR) or thalidomide (THAL) combination. We performed case matching with the continuous lenalidomide and dexamethasone (Rd continuous) arm of the FIRST trial and compared the associated clinical outcomes with FDT in a real-world setting.METHODSTNE patients treated in the real-world setting between 2009 and 2017 within Thames Valley Cancer Network (United Kingdom) were eligible to be included. Patient data from the real-world setting were matched by age cohorts and International Staging System (ISS) stage to patient-level data for Rd continuous from study MM-020. Data from 176 patients who received FDT in the real-world setting are presented here. The primary outcome measure was overall survival (OS), calculated as time from initiation of frontline treatment to death from any cause. Secondary endpoints included progression-free survival (PFS) and time to next treatment (TTNT). Treatment-free interval (TFI) was also explored in the FDT real-world group. Differences between Rd continuous and real-world FDT were tested using an unstratified log-rank test. The median OS and Cox hazard ratios, with 95% confidence intervals (CIs), were calculated and Kaplan-Meier survival estimates are presented.RESULTSThe combined data set comprised 442 TNE NDMM patients (Rd continuous, n = 266; FDT, n = 176). Patient characteristics were comparable between the 2 groups: male (Rd continuous, 58%; FDT, 60%), > 75 years (Rd continuous, 49.6%; FDT, 49.4%), ISS I/II (Rd continuous, 40.6%; FDT, 40.9%), ISS III (Rd continuous, 59.4%; FDT, 59.1%). FDT first-line therapy comprised proteasome inhibitor-based (23%), thalidomide-based (59%), lenalidomide-based (8%), and alkylator-based (10%) therapy. Rd continuous showed significantly improved OS compared with FDT (50.37 vs 31.11 months; HR = 0.65 [95% CI, 0.51-0.83]), PFS (21.85 vs 9.10 months; HR = 0.418 [95% CI, 0.33-0.53]), and TTNT (39.52 vs 18.3 months; HR = 0.41 [95% CI, 0.32-0.54]). The longest TFI during FDT was following first-line therapy (median, 7 months [IQR, 1.4-18.1 months]), decreasing to 2.4 months after second-line therapy (IQR, 0.8-6.3 months).CONCLUSIONSThis large, matched-cohort comparison of real-world TNE patients receiving FDT compared with continuous upfront Rd therapy confirms that Rd therapy provides significant benefit in terms of OS, PFS, and TTNT. In this comparison, the OS associated with Rd continuous was improved by over 19 months compared with FDT consisting of predominantly BOR or THAL combinations. This analysis also demonstrates that in the FDT cohort, the TFI is short after first-line therapy and decreases further with subsequent treatment. This analysis provides comparative evidence with real world-data and supports Rd continuous therapy as a new standard of care for patients with TNE MM. [Display omitted] DisclosuresDjebbari:Takeda: Honoraria; Celgene: Honoraria, Other: Educational Grant.. Lynes:Celgene: Employment, Equity Ownership, Other: educational grant awarded to Oxford Haematology Department. McLain-Smith:Celgene: Consultancy. Ramasamy:Amgen: Honoraria; Takeda: Honoraria, Research Funding; Janssen: Honoraria.