Enteroviral infection in patients treated with rituximab for non-Hodgkin lymphoma: a case series and review of the literature.

In recent years, anti-CD20 antibodies have been increasingly used to treat lymphoproliferative and immune disorders. Chronic viral infections are infrequently reported in patients receiving these therapies. Enteroviral infection can cause life-threatening meningoencephalitis and other systemic chronic syndromes in immune deficient patients. We describe the clinical courses and outcomes of 6 patients from 2 tertiary care institutions who developed chronic enteroviral infection with neurological manifestations, after combined chemoimmunotherapy with rituximab for B-cell lymphoma. We review the literature that includes 10 sporadic reported cases of chronic enteroviral meningoencephalitis attributed to rituximab therapy. It is a rare disease, and its diagnosis is often elusive. We propose that low immunoglobulin G levels are the main risk factor for developing chronic enteroviral infection and emphasize the need for a high index of suspicion, early diagnosis, and intervention in this iatrogenic and potentially fatal complication.

Safety and efficacy of FLAG-Ida-based therapy combined with venetoclax for the treatment for newly diagnosed and relapsed/refractory patients with AML - A systematic review.

Venetoclax (VEN) in combination with intensive chemotherapy (IC) is increasingly used to treat patients with high-risk acute myeloid leukemia (AML). We conducted a systematic review to assess the safety and efficacy outcomes of FLAG-IDA in combination with VEN. The primary safety outcome was infection rate; the primary efficacy outcome was response to treatment (composite complete remission (CRc) and overall response rate (ORR). Risk of bias was assessed according to the ROBINS-I tool. Six studies including 221 patients with newly-diagnosed (ND AML (n = 120)) and R/R AML (n = 101) disease, were included in this systematic review. Pooling of results was not conducted due to major differences between studies. The reported rates of neutropenic fever, bacteremia, pneumonia and invasive fungal infections were at 44-55 %, 24-48 %, 12-30 % and 11-36 % of assessed patients, respectively. Time to ANC and platelet recovery ranged between 23 and 29 and 23-31 days, respectively. Early death rate was 8.7 % (14/160) patients: four patients at 30 days, additional ten in 60 days. CRc rates ranged between 53 % and 78 % for R/R AML. CRc for ND was reported by one study only (89 %). ORR were reported in 60-78 % of patients with R/R AML. Only one study reported an ORR for ND patients of 98 %. In our systematic review, FLAG-Ida plus VEN proved to be a potentially tolerable and effective regimen in ND and R/R AML patients. We suggest further evaluation and confirmation for the safety and efficacy of this new protocol in future RCTs.

Maintenance therapy with hypomethylating agents for patients with acute myeloid leukemia in first remission not eligible for allogeneic hematopoietic cell transplantation: A systematic review and meta-analysis.

BACKGROUND: Older patients encompass about 75 % of patients with acute myeloid leukemia (AML). Today therapeutic options to prevent relapse in older patients who managed to achieve complete remission (CR) after intensive chemotherapy are scarce. Recent randomized controlled trials (RCTs) have aimed to reduce the risk of relapse by means of post-CR maintenance therapy. METHODS: We performed a systematic review and meta-analysis of RCTs comparing the efficacy and safety of maintenance with hypomethylating agents (HMA) vs. observation, conventional care or placebo in older patients with AML who are not candidates for allogeneic hematopoietic transplantation (allo-HCT). We searched Cochrane Library, PubMed and conference proceedings up to August 2021. RESULTS: Six trials were included. Treatment with hypomethylating agents significantly improved overall survival (HR 0.80, 95 % CI 0.70 to 0.91, I2 = 30 %), and disease control (HR 0.80, 95 % CI 0.70 to 0.91, I2 = 0). A significant decrease was seen in both one year mortality (Risk Ratio [RR] 0.61, 95 % CI 0.48 to 0.77, I2 = 0) and mortality at the end of follow-up (RR 0.77, 95 % CI 0.67 to 0.88, I2 = 0). The rate of relapse at 6 months and at one-two years was lower in the HMA arm vs. control (RR, 0.59; 95 % CI, 0.47-0.72; RR, 0.74, I2 = 0; 95 % CI 0.69 - 0.91, I2 = 41 %, respectively). HMA were associated with a statistically non-significant increase in the risk of serious adverse events (RR 3.44, 95 % CI 0.93-12.74, I2 = 80 %). CONCLUSIONS: Our meta-analysis shows that in older patients who are not candidates for allo-HCT, maintenance therapy with HMA improves OS and disease control without a statistically significant increase in adverse events.

Antibacterial prophylaxis with ciprofloxacin for patients with multiple myeloma and lymphoma undergoing autologous haematopoietic cell transplantation: a quasi-experimental single-centre before-after study.

OBJECTIVES: We aimed to study whether ciprofloxacin prophylaxis reduces infectious complications in patients undergoing autologous haematopoietic cell transplantation (AHCT). METHODS: This is a quasi-experimental, retrospective, before-after study. We compared the incidence of bacterial-related complications among 356 patients with multiple myeloma (MM) (n = 202) and lymphoma (n = 154) who underwent AHCT with (n = 177) or without (n = 179) ciprofloxacin prophylaxis between 03/2007 and 10/2012 and between 10/2012 and 07/2016, respectively, at a single centre. RESULTS: Febrile neutropaenia, bacteraemia, and pneumonia were significantly more common among patients who underwent AHCT during the second study period and did not receive antibacterial prophylaxis compared with patients who underwent AHCT during the first study period and received antibacterial prophylaxis (89.9% (161/179) vs. 83.1% (147/177), difference 6.9%, 95% CI 0-14.1%, P = 0.002; 15.1% (27/179) vs. 4.5% (8/177), difference 10.6%, 95% CI 4.4-16.9%, p < 0.0001; 12.3% (22/179) vs. 6.2% (11/177), difference 6.1%, 95% CI 0-12.3%, p = 0.04, respectively). The number-needed-to-treat to prevent one episode of bacteraemia, pneumonia, and febrile neutropaenia was 8.6, 8.5, and 13.7, respectively. Patients with ciprofloxacin prophylaxis had higher rates of ciprofloxacin-resistant bacteraemia (62.5% (5/8) vs. 18.5% (5/27), difference 44%, 95% CI 7-70%, p = 0.01). In multivariate analysis, ciprofloxacin prophylaxis significantly decreased the odds of bacteraemia (OR 0.19, 95% CI 0.07-0.52; p < 0.0001) and pneumonia (OR 0.37, 95% CI 0.16-0.85, p = 0.02). CONCLUSION: According to our single-centre experience, patients with MM and lymphoma undergoing AHCT may benefit from antibacterial prophylaxis with ciprofloxacin.

Graft-versus-leukemia in chronic lymphocytic leukemia.

Immune-mediated anti-leukemia effects, often termed graft-versus-leukemia (GvL), operate after bone marrow or blood cell transplants for acute lymphoblastic leukemia, acute myelogenous leukemia and chronic myelogenous leukemia. Sometimes the magnitude of this anti-leukemia effect exceeds that of high-dose anti-leukemia drugs and radiation and can result in leukemia cure. We analyzed leukemia relapse data after transplants for chronic lymphocytic leukemia (CLL) in this context. These data support the notion of a strong GvL effect in CLL. However, as most of these data are from studies of allotransplants, it is uncertain whether GvL operates in settings where the anti-leukemia effector cells and target CLL cells are genetically identical except for leukemia-related mutations. It is also uncertain whether GvL is distinct from GvHD. These potential limitations have important implications on whether immune therapy of CLL will work in non-allotransplant settings.

The MACOP-B and VACOP-B combination chemotherapy for young patients with intermediate-grade non-Hodgkin's lymphoma.

Since the early 1970s, three generations of combination chemotherapy for intermediate-grade non-Hodgkin's lymphomas (NHL) have been developed. One of the third-generation regimens is MACOP-B (methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin). The VACOP-B regimen is a modification of MACOP-B in which methotrexate is omitted and etoposide is added. This study assesses treatment outcome using the MACOP-B and VACOP-B combination chemotherapy in a population of young patients with intermediate-grade NHL treated in a single tertiary hematological center. The files of 45 patients aged 18-55 who were diagnosed as having intermediate-grade NHL (working formulation types F-H) and treated between January 1986 and March 1994 were reviewed. Treatment response, overall survival, disease-free survival and treatment toxicity were determined. The predictive value of the age-adjusted international prognostic index was also assessed. Median follow-up was 80 months in the MACOP-B group and 29 months in the VACOP-B group. The complete response rate was 71% (95% confidence interval CI: 58-84), 4-year overall survival was 74 +/- 7% and 4-year disease-free survival was 79 +/- 8%. No toxicity-related deaths were observed. The main adverse effects were WHO grade 3 or 4 neutropenia (51%), anemia (24%) and mucositis (20%). Only the CR rate was correlated with the Age-Adjusted International Prognostic Index. Mean relative dose intensity was high (95.7%, 95%) CI: 91.7-99.7) and had no correlation with treatment outcome. The MACOP-B and VACOP-B combination chemotherapy regimens were found to be effective and minimally toxic for young patients up to 55 years old with intermediate-grade NHL.

Postremission therapy with two different dose regimens of cytarabine in adults with acute myelogenous leukemia.

Sixty-seven out of 105 (64%) adults with de novo acute myelogenous leukemia (AML), achieving complete remission after induction chemotherapy, entered two successive postremission treatment protocols. Between 1987 and 1989, 35 patients received an intermediate dose of cytarabine (IDAC) along with other drugs. Between 1990 and 1993, 32 patients received high dose cytarabine (HIDAC) with similar other drugs. Patients treated with IDAC had a median survival of 13.8 months (95% CI 11.2-23.1 months) and a 2 year survival of 34.3 +/- 8.0%. Patients receiving HIDAC had a median survival of 35.5 months (95% CI, lower limit 29.8 months) and a 2 year survival of 71.6 +/- 9.4% (P < 0.002). The 2 year actuarial leukemia-free survival (LFS) was 17.8 +/- 6.6% in the IDAC group and 67.3 +/- 10.0% months in the HIDAC group (P = 0.004). The HIDAC group had a significant 2 year survival advantage over the IDAC group only in patients younger than 45 years. The 2 year survival in the first group was 83.3 +/- 10.8% versus 23.5 +/- 10.3% in the IDAC group (P = 0.0001). In patients older than 45 years, no significant differences in 2 year survival was noticed (52.9 +/- 15.78 versus 44.4 +/- 11.7, P = 0.8). Censoring the 21 patients who underwent bone marrow transplantation (BMT) at BMT did not change significantly the survival analysis of the patients in each group. This study is consistent with previous reports favoring HIDAC intensification in the postremission treatment of young patients with AML.

Salvage therapy of refractory and relapsed acute leukemia with high dose mitoxantrone and high dose cytarabine.

We have assessed the outcome of 66 refractory and relapsed acute leukemia patients treated with high dose mitoxantrone and cytarabine. Therapy consisted of a total dose of 40-60 mg/m2 mitoxantrone and 3 g/m2 of cytarabine daily on 5 consecutive days. A total of 28 patients were treated for primary resistant and 38 patients for early or late relapsed leukemia. A total of 35 patients achieved CR. Four patients died during the induction course. Toxicity was acceptable and comparable to other salvage regimens. The median disease-free and overall survivals were 4 and 6 months, respectively. Although this regimen is effective in achieving remission in refractory leukemia, its duration is short.

Engraftment-associated hypophosphatemia--the role of cytokine release and steep leukocyte rise post stem cell transplantation.

Hypophosphatemia associated with bone marrow transplantation has been infrequently reported. The suggested mechanism is phosphate uptake by the replicating cells. Various cytokines are associated with the development of hypophosphatemia. The present study evaluated the interrelationship between cytokine release, the rise in WBC and the development of hypophosphatemia during the engraftment period. Blood samples were obtained from 60 patients undergoing peripheral blood stem cell transplant, on the day of admission and then daily from the day of transplant until discharge. Hypophosphatemia developed in 62% of the patients. The median day of minimal phosphorus level was +8 and it antedated engraftment by 2 days. There was a significant correlation between the day of minimal phosphorus level and the day of maximal WBC and a significant correlation between the fall in phosphorus level and WBC rise. IL-6 and IL-8 showed similar kinetics. Higher IL-6 and IL-8 levels were directly associated with lower phosphorus levels. In conclusion, hypophosphatemia commonly occurs in the post-transplant period. We assume that both a direct effect of cytokine release and an increased consumption by the dividing WBCs contribute to its appearance. As its occurrence usually antedates engraftment it can be used as a forerunner for WBC recovery.

Plasma cell dyscrasia with polyneuropathy--POEMS syndrome presenting with vasculitic skin lesions and responding to combination chemotherapy.

We report a 61-year-old male patient who presented with severe sensorimotor neuropathy, leg edema and skin lesions with M-paraprotein and 50% plasma cells in the bone marrow. The POEMS (Crow-Fukase) syndrome was diagnosed and the skin lesions were compatible with vasculitis according to the histopathology. The patient was treated with aggressive combined chemotherapy, which induced improvement in both the clinical and laboratory parameters of his disease. To the best of our knowledge this is the first report of a vasculitic process underlying the skin changes in the POEMS syndrome. Our findings may shed light on the unknown pathogenesis of this syndrome and the successful results of treatment support the adoption of an aggressive therapeutic approach in symptomatic patients.

Extramedullary progression despite a good response in the bone marrow in patients treated with thalidomide for multiple myeloma.

We report two patients who were treated with thalidomide for resistant multiple myeloma (MM) and developed extramedullary plasmacytomas despite a good response in the bone marrow. The first patient had progressive disease 18 months post autologous peripheral stem cell transplant. Two and a half months after the initiation of thalidomide therapy extensive new plasmacytomas of the skin and nasal mucosa appeared while the medullary response continued. The second patient was treated with thalidomide for resistant MM. Despite a medullary response he developed neurological signs compatible with cranial nerve involvement and an MRI study was suggestive of a plasmacytoma involving the sellar region. We assume that a change in the expression of some adhesion molecules on the myeloma and/or the stromal cells is responsible for this phenomenon. Treating Physicians should be aware of this phenomenon in MM patients receiving thalidomide.

Acute neutrophilic dermatosis induced by all-trans-retinoic acid treatment for acute promyelocytic leukemia.

All-trans-retinoic acid (ATRA) is considered the recommended induction treatment for acute promyelocytic leukemia (APL). Although the dermatological side effects associated with ATRA treatment are relatively common, acute neutrophilic dermatosis (Sweet's syndrome) has only been rarely reported. We describe such a case who responded to chemotherapy and not to low doses of corticosteroids.

Diffuse alveolar hemorrhage in acute promyelocytic leukemia patients treated with ATRA--a manifestation of the basic disease or the treatment.

All-trans-retinoic acid (ATRA) is considered the recommended induction treatment for acute promyelocytic leukemia. In the pre-ATRA era pulmonary bleeding was a common cause of death in these patients, mostly due to disseminated intravascular coagulation which was further exacerbated by the administration of chemotherapy. Although ATRA syndrome, the most serious adverse effect of ATRA treatment, involves the lungs, pulmonary hemorrhage has only rarely been reported as a manifestation of ATRA syndrome. Here we describe 2 patients who developed diffuse alveolar hemorrhage during treatment with ATRA. The possible mechanisms of pulmonary bleeding in these cases are discussed.

[Treatment of adults with acute lymphoblastic leukemia--results at the Sheba Medical Center, Tel-Hashomer, 1977-1988].

Acute lymphoblastic leukemia (ALL) is a malignant disease whose incidence is relatively low among adults, unlike in children. Adults with ALL have a lower rate of long-term disease-free survival. During the last 20 years, a German multicenter group has shown that their protocols have achieved good results in adults ALL. We reviewed the medical records of 35 ALL patients, aged 19-63 years, whom we treated with these protocols (1988-1997). The remission rate was 94%. At a median follow-up of 46 months the 2-year overall survival was 54% and the disease-free survival was 94%. Although 2 patients died of bone marrow transplant complications, no death was directly associated with drug toxicity. The main grade 3 or 4 side effects (WHO classification) were neutropenia (91%), thrombocytopenia (71%) and anemia (71%). With there protocols we achieved high overall and disease-free survival rates, especially in comparison with other reports. Despite the high rate of severe treatment toxicity, there were no fatalities directly related to treatment. These results emphasize the need to concentrate treatment of adult ALL patients in large medical centers with expertise in the use of the complicated treatment protocols required.

[High-dose chemotherapy and autologous stem cell transplantation for refractory and relapsing Hodgkin's disease as first-line therapy-- studies at Sheba Medical Center--Tel Hashomer].

High dose chemotherapy and autologous stem cell transplantation are widely used in relapsed and primary refractory Hodgkin's disease. We transplanted 42 patients with Hodgkin's disease between 1990-1998. Median follow-up was 31 months (range 1-102). 29 (69%) were transplanted after relapse and 13 (31%) were refractory to first line therapy. Median age at transplantation was 29 years (range 19-58) and 23 (55%) were males. All were treated with the BEAM protocol (carmustine, etoposide, cytarabine and melphelan). 18 who were in remission received radiotherapy following transplantation. The source of the stem cells was bone marrow in 17% and peripheral blood in 83%. At initial diagnosis: 57% had stage III-IV disease and B symptoms were present in 52%. 75% were treated with MOPP, ABVD or with related versions. Radiotherapy followed in 52%. Prior to transplantation, 45% of the relapsed group were in the advanced stage. 33% and 12% of all patients had lung and bone involvement, respectively. The complete remission rate was 86% for the 2 groups. 2 (5%) died from transplant-related complications and MDS/AML developed in 2 (5%) after transplantation. The 3-year overall survival (OS) and disease-free survival (DFS) were 68% and 60%, respectively. The 3-year OS for the relapsed group was 64% compared with 76% for the refractory group, and the 3-year DFS for the relapsed group was 60% vs. 42% for the refractory group (neither difference significant). Radiotherapy following transplantation did not have a beneficial effect on DFS. No prognostic factors for outcome of transplantation were found, most probably due to the limited number of patients and the high variability of disease characteristics. We conclude that high dose chemotherapy and autologous stem cell transplantation are effective and relatively safe for relapsed or primary refractory Hodgkin's disease. The DFS at 3 years was longer for those transplanted after relapse than those with primary refractory disease, but not significantly. Patients with primary refractory disease can be salvaged with high dose chemotherapy.