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Concept: Hematological malignancy

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Increasing knowledge concerning the biology of hematologic malignancies as well as the role of the immune system in the control of these diseases has led to the development and approval of immunotherapies that are resulting in impressive clinical responses. Therefore, the Society for Immunotherapy of Cancer (SITC) convened a hematologic malignancy Cancer Immunotherapy Guidelines panel consisting of physicians, nurses, patient advocates, and patients to develop consensus recommendations for the clinical application of immunotherapy for patients with multiple myeloma, lymphoma, and acute leukemia. These recommendations were developed following the previously established process based on the Institute of Medicine’s clinical practice guidelines. In doing so, a systematic literature search was performed for high-impact studies from 2004 to 2014 and was supplemented with further literature as identified by the panel. The consensus panel met in December of 2014 with the goal to generate consensus recommendations for the clinical use of immunotherapy in patients with hematologic malignancies. During this meeting, consensus panel voting along with discussion were used to rate and review the strength of the supporting evidence from the literature search. These consensus recommendations focus on issues related to patient selection, toxicity management, clinical endpoints, and the sequencing or combination of therapies. Overall, immunotherapy is rapidly emerging as an effective therapeutic strategy for the management of hematologic malignances. Evidence-based consensus recommendations for its clinical application are provided and will be updated as the field evolves.

Concepts: Immune system, Medicine, Cancer, Bone marrow, Chemotherapy, Types of cancer, Leukemia, Hematological malignancy

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The prognosis for fit patients with mantle cell lymphoma has improved with intensive strategies. Currently, the role of maintenance/consolidation approaches is being tested as relapses continue appearing. In this trial we evaluated the feasibility, safety and efficacy of R-Hyper-CVAD alternating with R-MtxAraC followed by consolidation with 90Y-Ibritumomab-Tiuxetan. Patients received 6 cycles followed by a single dose of 90Y-Ibritumomab-Tiuxetan. Thirty patients were enrolled. Median age was 59 years. Twenty four patients finished the induction treatment, 23 achieved complete remission (77%, 95% confidence interval 60-93) and one patient had progressive disease (3%). Eighteen patients (60%), all in complete remission, received consolidation. In the intent- to- treat population, failure free, progression free and overall survival at 4 years were 40 % (95% confidence interval 20.4-59.6), 52% (95% confidence interval 32.4-71.6) and 81% (95% confidence interval 67.28-94.72), respectively. For patients who received consolidation, failure free and overall survival were 55% (95% confidence interval 31.48&-78.52) and 87% (95% confidence interval 70-100), respectively. Hematological toxicity was significant during induction and responsible for one death (3.3%). After consolidation, grade 3-4 neutropenia and thrombocytopenia were observed in 72% and 83% of patients, with median duration of 5 and 12 weeks, respectively. Six (20%) patients died, 3 due to secondary malignancies (myelodisplastic syndrome and bladder and rectum carcinomas). In conclusion, our experience with R-Hyper-CVAD/R-MtxAraC followed by consolidation with 90Y-Ibritumomab-Tiuxetan is efficacious although less feasible than expected. The unacceptable toxicity observed, specially secondary malignancies, advise against the indication of this strategy. Trial registration: clinical.gov identifier: NCT2005-004400-37.

Concepts: Cancer, Lung cancer, Chemotherapy, Types of cancer, Interval finite element, Normal distribution, Hematological malignancy, Mantle cell lymphoma

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Cachexia in patients with hematological malignancies is often related to sarcopenia. We believe that allogeneic hematopoietic stem cell transplant (allo-HSCT) patients often exhibit sarcopenia prior to transplantation. Here, we aimed to investigate the prevalence of sarcopenia and its relationship with body composition, physiological function, nutrition, fatigue, and health-related quality of life (QOL) in patients before allo-HSCT. We further investigated the confounding factors associated with sarcopenia.

Concepts: Cancer, Bone marrow, Chemotherapy, Hematology, Organ transplant, Hematopoietic stem cell transplantation, Hematopoietic stem cell, Hematological malignancy

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Pulmonary mucormycosis (PM) is a life-threatening opportunistic mycosis with a variable clinical evolution and few prognostic markers for outcome assessment. Several clinical risk factors for poor outcome present at the diagnosis of PM were analyzed in 75 consecutive hematology patients from 2000-2012. Significant variables (P < 0.1) were entered into a multivariate Cox-proportional hazard regression model adjusting for baseline APACHE II to identify independent risk factors for mortality within 28 days. Twenty-eight of 75 patients died within 4-week follow up. A lymphocyte count < 100/mm(3) at the time of diagnosis (adjusted hazard ratio 4.0, 1.7-9.4, P = 0.01) and high level of lactate dehydrogenase (AHR 3.7, 1.3-10.2, P = 0.015) were independent predictors along with APACHE II score for 28-day mortality. A weighted risk score based on these 3 baseline variables accurately identified non-surviving patients at 28 days (area under the receiver-operator curve of 0.87, 0.77-0.93, P < 0.001). A risk score > 22 was associated with 8-fold high rates of mortality (P < 0.0001) within 28 days of diagnosis and median survival of 7 days versus ≥28 days in patients with risk scores ≤22. We found that APACHE II score, severe lymphocytopenia and high LDH levels at the time of PM diagnosis were independent markers for rapid disease progression and death.

Concepts: Epidemiology, Death, Medical statistics, Risk, Leukemia, Blood disorders, Lactate dehydrogenase, Hematological malignancy

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Methotrexate (MTX) is an effective treatment for childhood acute lymphoblastic leukemia (ALL) or Non-Hodgkin lymphoma (NHL); however, toxicity can arise with high doses MTX (HDMTX), especially in patients with delayed MTX elimination. Routine monitoring of plasma MTX concentrations is clinically important, but unfortunately is not always feasible. The aim of this study was to examine the relationship between MTX elimination and renal function to identify parameters that may be useful for predicting delayed MTX elimination in Chinese children with ALL and NHL. A total of 105 children with ALL and NHL were included in the study. Each patient received HDMTX (3 or 5 g/m2) over 24 hours. Plasma MTX concentrations were measured at 24, 48, and 96 hours. Delayed elimination was indicated by plasma MTX concentrations ≥1.0 at 48 hours or ≥0.1 μmol/L at 96 hours. Creatinine clearance rate (CCr) and serum Cr concentrations were measured at 0, 24, and 48 hours. There were 39 patients (37.1%) with delayed MTX elimination. For patients with delayed MTX elimination, the 24 hour plasma MTX concentration was negatively correlated with the 24 hour CCr (P=0.019). The 48 hour plasma MTX concentration was positively correlated with 24 and 48 hour serum Cr concentrations (P=0.001 and P<0.001, respectively), and negatively correlated with the 24 and 48 CCr (both P<0.001). Both MTX concentrations and elimination time decreased with increasing CCr (P<0.05 and P<0.001, respectively). Receiver operating characteristic curves revealed that the best predictors of delayed MTX elimination were 24 hour CCr 36 mmol/L (sensitivity: 64.7%; specificity: 77.4%) (both P < 0.001). CCr and serum Cr concentration may be useful for monitoring plasma MTX concentrations in children receiving HDMTX for ALL and NHL and for predicting delayed MTX elimination. Keywords: Acute lymphoblastic leukemia, Child, Creatinine clearance, Kidney function, Methotrexate, non-Hodgkin lymphoma, Pharmacokinetics.

Concepts: Renal failure, Nephrology, Renal physiology, Renal function, Blood urea nitrogen, Acute lymphoblastic leukemia, Hematological malignancy, Creatinine clearance

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Passenger lymphocyte syndrome (PLS) presents as transient immune hemolysis due to anti-recipient ABO antibodies produced by donor B-lymphocytes accompanying minor or bidirectional ABO incompatible allogeneic hematopoietic stem cell transplantation (HSCT). We monitored both IgM and IgG type anti-recipient ABO antibodies in 18 consecutive HSCT recipients with hematological malignancies. Five of these patients (28 %) developed transient immune hemolysis due to PLS after a median of 19 days post-HSCT. This response was associated with the detection of IgM and IgG anti-recipient ABO antibodies after a median of 16 and 22 days post-HSCT, respectively. All five patients subsequently developed acute graft-versus-host disease (GVHD) grades II-IV, and three died due to transplant-related mortality (TRM) within 1 year after HSCT, while in contrast, of the 13 patients without PLS, three (23 %) developed grades II-IV acute GVHD (p < 0.01) and the 1-year TRM was 8 % (p = 0.03). Thus, patients with PLS had a significantly lower 1-year overall survival than those without PLS (20 vs. 75 %, p = 0.03). These findings suggest that the IgM anti-recipient ABO antibody may be an early predictor of acute GVHD and poor survival after minor or bidirectional ABO incompatible HSCT.

Concepts: Immune system, Antibody, Blood type, Immunology, Graft-versus-host disease, Hematopoietic stem cell transplantation, Transplantation medicine, Hematological malignancy

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BACKGROUND: :Allogeneic stem cell transplantation is the most effective treatment option for many hematological malignancies, but graft-versus-host-disease (GvHD) remains a major cause of treatment failure. Besides well established risk factors for the outcome of transplantation, recent single-center studies have identified a birth order effect in HLA-identical sibling stem cell transplantation with lower incidence of acute and chronic extensive graft-versus-host disease (aGvHD/ cGvHD) and improved overall survival when a donor is younger than the recipient. One hypothesized mechanism is microchimerism due to fetomaternal and transmaternal sibling cell trafficking during pregnancy as the donor is exposed to recipient antigens in utero. DESIGN: and Methods: The aim of this study was to validate single-center data in a multicenter cohort provided by the Center for International Blood and Marrow Transplantation (CIBMTR). All adult and pediatric patients (n=11,365) with a diagnosis of a hematologic malignancy receiving an allogeneic stem cell transplantation from an HLA-identical sibling donor from 1990 to 2007 were included. RESULTS: When donors were younger than recipients, there was a significantly lower aGvHD II-IV° and cGvHD rate for children as well as lower cGvHD rate for adolescents. However, the hypothesized overall positive effect of lower relapse and better survival when donors are younger than recipients was not observed in this large multicenter study. CONCLUSIONS: Our data suggest that if otherwise equally matched, a graft from a sibling younger than the patient may be superior to an older one for child and adolescent stem cell transplant patients.

Concepts: Oncology, Chemotherapy, Graft-versus-host disease, Hematology, Organ transplant, Hematopoietic stem cell transplantation, Transplantation medicine, Hematological malignancy

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Most patients with indolent B-cell lymphomas fail to achieve complete remission with current treatment approaches and invariably relapse. During the past decade, innovative immunochemotherapy strategies have substantially improved disease control rates but not survival, thus providing the rationale for development of novel agents targeting dysregulated pathways that are operable in these hematological malignancies. Ibrutinib, a novel first-in-human Bruton’s tyrosine kinase (BTK) inhibitor, has progressed into phase III trials after early-phase clinical studies demonstrated effective target inhibition, increased tumor response rates, and significant improvement in survival, particularly in patients with indolent B-cell lymphomas. Recently, the compound was designated a “breakthrough therapy” by the United States Food and Drug Administration for the treatment of patients with relapsed or refractory mantle cell lymphoma and Waldenström macroglobulinemia. This review summarizes recent achievements of ibrutinib, with a focus on its emerging role in the treatment of patients with indolent B-cell lymphoid malignancies.

Concepts: AIDS, Clinical trial, Cancer, United States, Types of cancer, Lymphoma, Hematological malignancy, Mantle cell lymphoma

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Mantle cell lymphoma (MCL) is a mature B-cell malignancy that continues to have a high mortality rate. In this article, we discuss key pathogenic pathways in MCL biology and their possible therapeutic targeting.

Concepts: Protein, Cancer, Mortality rate, B cell, Lymphoma, Hematological malignancy, Mantle cell lymphoma, B-cell lymphoma

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Background Recently, due to inadequacies during immediate management of patients with febrile neutropenia, a new gold standard ‘door-to-needle’ time of 1 hour for the administration of intravenous antibiotics was introduced. Objective The aim of this audit was to identify whether that target was being met in our emergency department (ED). This is phase 1 of the study which will be followed by identification of barriers to the achievement of the target and recommendations for improvement. Materials and methods Data were collected from January 2013 to April 2013 of consecutive patients (adult and pediatric age group) who presented to the ED with febrile neutropenia for various underlying causes. Fever was defined as single oral temperature of >38.3°C (101°F) or a temperature of >38.0°C (100.4°F) sustained for more than 1 hour. Neutropenia was defined as absolute neutrophil count <0.5 × 10(9)/l, or expected to fall below that number. Variables analyzed included age, gender, antibiotics administered, underlying diagnosis, day of presentation, and door-to-needle time. Results During the study period, there were n = 81 patients who presented with febrile neutropenia. There were n = 49 were males and n = 32 were females. There were n = 37 patients in the pediatric age group while rest were adults. Patients most commonly had an underlying hematological malignancy (n = 49). A combination of piperacillin/tazobactam (4.5 g × Q8hrly) and amikacin (750 mg × once daily) was most frequently administered (n = 57) to these patients. The median door-to-needle time was 45 minutes (range ± SD: 10 minutes to 6 hours ± 1 hour 10 minutes). Long delays of over 4 hours occurred in n = 4 patients (all were adults). There were minimal delays observed in pediatric patients due to 'red alert' policy implementation. Long delays occurred on weekdays and weekends, equally. Conclusion The overall median door-to-needle time was 45 minutes, which was in the accepted range. However, delays that occurred demand improvements like introducing 'red alert' policy for adult patients, counseling of staff and residents, identifying potential barriers in achieving the target time along with solutions, and developing hospital-based guidelines on managing patients with neutropenic sepsis.

Concepts: White blood cell, Oncology, Hematology, Fever, Hematological malignancy, Neutropenia, Absolute neutrophil count, Febrile neutropenia