Paraneoplastic syndromes associated with classic Hodgkin lymphoma, a systematic literature review.

PNS are uncommon manifestations of cancer. The current literature about these syndromes in the setting of cHL is disintegrated. A systematic literature review of all published literature was conducted. One hundred twenty-eight patients from 115 publications met the inclusion/exclusion criteria. Eight-five patients were of the NS subtype (66.4%). The most frequent clinical presentation of the PNS was CNS manifestation (25.8%). The majority of patients were diagnosed with the cHL and PNS simultaneously (42.2%). In 33.6% of patients, the lymphoma diagnosis preceded the PNS diagnosis. In 16.4% of patients, the PNS diagnosis preceded the lymphoma diagnosis. The presence of PNS antibodies was reported in 35 patients (27.3%). Age older than 18 was associated with higher prevalence of PNS. The CR rate of the lymphoma was 77.3%. The complete resolution rate of the PNS was 54.7%. Relapse of lymphoma was reported in 13 patients, and recurrence of the PNS upon relapse was reported in 10/13 patients.

Incidence and risk factors for secondary graft failure in uniformly treated patients with severe aplastic anemia receiving fludarabine and cyclophosphamide for conditioning and matched sibling bone marrow graft as stem cell source.

BACKGROUND AIMS: Graft failure after allogeneic transplant for aplastic anemia is problematic. The risk of graft failure depends on multiple variables, including the preparative regimen, donor type, stem cell dose and source among other variables. METHODS: We performed a retrospective analysis of patients with aplastic anemia who underwent matched-sibling allogeneic transplant at a single center. RESULTS: We identified 82 patients who fit the inclusion criteria. One had primary graft failure and was excluded from this analysis. The recipient median age was 22 years. The donor median age was 23 years. The median time from diagnosis to transplant was 1.6 months. The median number of red cell transfusions before transplant was nine. The median number of platelet transfusions before transplant was 18. Thirteen patients developed secondary graft failure, with a cumulative incidence at 5 years of 16% and median time to develop secondary graft failure of 129 days. All patients engrafted with a median time for neutrophil engraftment of 19 days and a median time for platelet engraftment of 22 days. The survival of patients with or without secondary graft failure was not different. Major or bidirectional ABO incompatibility and older recipient age were statistically significantly associated with greater risk of secondary graft failure. CONCLUSIONS: Secondary graft failure is a significant complication after allogeneic transplant for SAA. Identification of recipients at risk and mitigating the potential risks of this complication is warranted.

Frontline-matched sibling donor transplant of aplastic anemia patients using primed versus steady-state bone marrow grafts.

Priming donors with G-CSF before BM harvest is reported to improve engraftment and GvHD in recipients. These effects are highly desirable when transplanting patients with non-neoplastic hematologic diseases, particularly AA patients. Here we retrospectively report the outcomes of 39 AA patients receiving a primed BM graft from MSD to 43 patients receiving a steady-state BM graft from MSD, otherwise transplanted using a uniform transplant platform. The graft had higher TNC and CD34 cell concentrations in the primed group (p < 0.001), and that was reflected in higher TNC and CD34 doses per kilogram of recipient in the primed group (p = 0.004 and 0.03, respectively). The OS for primed BM graft recipients was 97.4% and 78.9% for the steady-state BM graft recipients, p-value = 0.01. The cumulative incidence of death without GF was 2.6% in the primed group and 16.3% in the steady-state group, p-value = 0.03. There was no difference in GvHD incidence between the two groups. We confirm that priming improved the TNC and CD34 graft concentration and cell dose; this evidence along with other reported studies constitute reasonable evidence to prove that BM priming improve engraftment. We observed no increase in GvHD using primed BM graft.

Follicular lymphoma grade 3: a comprehensive review.

Follicular lymphoma (FL) is a heterogeneous entity with disparate outcomes based on clinical and pathologic characteristics. An increasingly detailed understanding of high-grade FL (grade 3) has led to the identification of separate categories of FL3A and FL3B. Recently, genomic studies have made much progress in delineating the genetic differences between FL3A and FL3B. Although a general consensus exists that FL3B follows an aggressive course matching that of diffuse large B-cell lymphoma, there is less certainty regarding the course of FL3A. Uncertainty also exists regarding the management of high-grade FL. Given that a majority of the prospective landmark trials in FL have excluded patients with high-grade FL, most of the available evidence is retrospective. This review summarizes the recent advances in the management of high-grade FL.

Hematopoietic Cell Transplant Consideration for Philadelphia Chromosome-Like Acute Lymphoblastic Leukemia Patients.

Philadelphia chromosome-like (Ph-like) acute lymphoblastic leukemia (ALL) is a relatively new entity characterized by high cytokine receptor and tyrosine kinase signaling resulting in multiple downstream pathway stimulation. The standard diagnostic method, gene expression profiling, is not widely available. Efforts are ongoing to establish easy and clinically applicable diagnostic pathways to facilitate the accurate identification of these patients and thus enable a better understanding of the prognosis and outcomes with different treatment approaches. The rates of complete remission in ALL patients are consistently above 90% with the different induction protocols; however, maintaining remission depends on the risk group of the patient and consolidation therapy. Allogeneic hematopoietic cell transplant (allo-HCT) is particularly beneficial when the risk of relapse is very high and the expected complications with transplant are low. Data on the outcomes of allo-HCT for Ph-like ALL are scarce. In this article we review the published literature on outcomes of Ph-like ALL patients treated using different therapeutic approaches and make recommendations about transplant consideration for these patients.

Current paradigms in the management of Philadelphia chromosome positive acute lymphoblastic leukemia in adults.

Philadelphia chromosome-positive (Ph-positive) acute lymphoblastic leukemia (ALL) is a biologically, clinically, and genetically distinct subtype of precursor-B ALL. The Ph chromosome, results from a reciprocal translocation of the ABL1 kinase gene on chromosome 9 to the breakpoint cluster region (BCR) gene on chromosome 22. Depending on the translocation breakpoint, typically a p210 BCR-ABL1 or a p190 BCR-ABL onc protein are generated; both are constitutively active tyrosine kinases that play a central role to alter signaling pathways of cell proliferation, survival, and self-renewal, leading to leukemogenesis. In Ph-positive ALL, the p190-BCR-ABL (minor [m]-bcr) subtype is more frequent than the p210-BCR-ABL (major [M]-bcr) subtype, commonly found in chronic myeloid leukemia. The Philadelphia chromosome is the most frequent recurrent cytogenetic abnormality in elderly patients with ALL. Its incidence increases with age, reaching ∼50% in patients with ALL aged 60 years and over. Patients traditionally had a very poor outcome with chemotherapy, particularly if they do not undergo allogeneic hematopoietic cell transplantation (allo-HCT) in first complete remission (CR1). With the availability of multiple tyrosine kinase inhibitors (TKI), the therapeutic armamentarium is expanding quickly. However, there is no consensus on how to best treat Ph-positive ALL. With modern therapy, improved outcomes have led to the emergence of a number of controversies, including the need for intensive chemotherapy, the ideal TKI, and whether all eligible patients should receive an allo-HSCT, and if so, what type. Here, we discuss these controversies in light of the available literature.

Refining the Role of Hematopoietic Cell Transplantation for Acute Lymphoblastic Leukemia as Novel Therapies Emerge.

Acute lymphoblastic leukemia (ALL) is a rare adult neoplasm. The disorder consists of precursor B or T phenotypes. In the pediatric population, ALL was a success story in that 80% of children with ALL enjoy long-term survival. In adults, similar complete remission rates are achieved with current induction regimens; however, less than 50% of patients are alive at 5 years, with most deaths due to relapsed disease. Accordingly, optimizing post remission consolidation therapy might improve in outcomes. Such strategies may include chemotherapy and autologous or allogeneic transplant. Moreover, the ability to modify such therapy based on better disease risk stratification while taking into account patient characteristics such as performance status and presence of comorbidities is necessary to tailor treatment accordingly. Here, we review available medical literature on the use of hematopoietic cell transplantation as a consolidation modality in the treatment of adult ALL.

Treatment with Hypomethylating Agents before Allogeneic Stem Cell Transplant Improves Progression-Free Survival for Patients with Chronic Myelomonocytic Leukemia.

The treatment of patients with chronic myelomonocytic leukemia (CMML) with transplant has not been optimized. We retrospectively reviewed the data for 83 consecutive patients with CMML (47 with CMML-1/2 and 36 with CMML progressed to acute myeloid leukemia) who received an allogeneic stem cell transplant (allo-SCT) at our institution between April 1991 and December 2013 to identify factors associated with improved survival and determine whether treatment with hypomethylating agents before transplant improves progression-free survival (PFS). The median age of the cohort was 57 years. Seventy-eight patients received induction treatment before transplant, with 37 receiving hypomethylating agents and 41 receiving cytotoxic chemotherapy. Patients treated with a hypomethylating agent had a significantly lower cumulative incidence of relapse at 3 years post-transplant (22%) than those treated with other agents (35%; P = .03), whereas treatment-related mortality at 1 year post-transplant did not significantly differ between the groups (27% and 30%, respectively; P = .84). The lower relapse rate resulted in a significantly higher 3-year PFS rate in patients treated with a hypomethylating agent (43%) than in those treated with other agents (27%; P = .04). Our data support the use of hypomethylating agents before allo-SCT for patients with CMML to achieve morphologic remission and improve PFS of these patients. Future studies are needed to confirm these findings.

Results of a 2-arm, phase 2 clinical trial using post-transplantation cyclophosphamide for the prevention of graft-versus-host disease in haploidentical donor and mismatched unrelated donor hematopoietic stem cell transplantation.

BACKGROUND: High-dose, post-transplantation cyclophosphamide (PTCy) to prevent graft-versus-host disease (GVHD) has improved outcomes in haploidentical (HAPLO) stem cell transplantation (SCT). However, it remains unclear whether this strategy is effective in SCT from 1-antigen human leukocyte antigen (HLA)-mismatched unrelated donors (9/10 MUD) and how the outcomes of these patients compare with those of haploidentical transplantation recipients. METHODS: A parallel, 2-arm, nonrandomized phase 2 clinical trial was conducted of melphalan-based reduced-intensity conditioning with PTCy, tacrolimus, and mycophenolate mofetil to prevent GVHD in patients with high-risk hematologic malignancies who underwent HAPLO (n = 60) or 9/10 MUD (n = 46) SCT. RESULTS: The 1-year overall and progression-free survival rates were 70% and 60%, respectively, in the HAPLO arm and 60% and 47%, respectively, in the 9/10 MUD arm. The day +100 cumulative incidence of grade II to IV acute GVHD and grade III to IV acute GVHD was 28% and 3%, respectively, in the HAPLO arm and 33% and 13%, respectively, in the 9/10 MUD arm. The 2-year cumulative incidence of chronic GVHD was 24% in the HAPLO arm and 19% in the 9/10 MUD arm. The 1-year cumulative incidence of nonrelapse mortality was 21% in the HAPLO arm and 31% in the 9/10 MUD arm, and the 1-year relapse rate was 19% in the HAPLO arm and 25% in the 9/10 MUD arm. CONCLUSIONS: Although this was a nonrandomized study and could not serve as a direct comparison between the 2 groups, the authors conclude that PTCy-based GVHD prophylaxis is effective for both HAPLO and 9/10 MUD SCTs. Prospective randomized trials will be required to compare the efficacies of alternative donor options for patients lacking HLA-matched donors. Cancer 2016;122:3316-3326. © 2016 American Cancer Society.

Outcome of Patients with Immunoglobulin Light-Chain Amyloidosis with Lung, Liver, Gastrointestinal, Neurologic, and Soft Tissue Involvement after Autologous Hematopoietic Stem Cell Transplantation.

There is limited information on the outcome when organs other than heart or kidneys are involved by immunoglobulin light-chain amyloidosis (AL). We report the outcome of 53 patients with AL with gastrointestinal (GI), peripheral nerve (PN), liver, lung, or soft-tissue involvement, who underwent high-dose chemotherapy and autologous hematopoietic stem cell transplantation (auto-HCT) at our institution between 1997 and 2013. The median age at auto-HCT was 56 years (range, 35 to 74). One, 2, 3, or 4 organs were involved in 43%, 22%, 28%, and 4% of patients, respectively. Concurrent cardiac, renal, or both were involved in 24 (45%) patients. Forty-six patients received induction therapy before auto-HCT. The 100-day and 1-year treatment-related mortality (TRM) were 3.8% (n = 2) and 7.5% (n = 4), respectively. Forty-one (80%) patients achieved a hematologic response. Organ response at 1 year after auto-HCT was seen in 23 (57%) of the 40 evaluable patients. With a median follow-up of 24 months, the median progression-free survival and overall survival (OS) were 36 and 73 months, respectively. Auto-HCT was associated with a low TRM, durable organ responses, and a median OS of > 6 years in selected patients with AL and GI, PN, liver, lung, or soft-tissue involvement.

A comprehensive review of the role of bone marrow biopsy and PET-CT in the evaluation of bone marrow involvement in adults newly diagnosed with DLBCL.

Diffuse large B cell lymphoma (DLBCL) is one of the most prevalent subtypes of non-Hodgkin lymphoma (NHL) and is known for commonly infiltrating extra-nodal sites. The involvement of the bone marrow by lymphoma cells significantly impacts the staging, treatment, and prognosis among the extra-nodal sites in DLBCL. Bone marrow biopsy has been considered the standard diagnostic procedure for detecting bone marrow involvement. However, advancements in imaging techniques, such as positron emission tomography-computed tomography (PET-CT), have shown an improved ability to detect bone marrow involvement, making the need for bone marrow biopsy debatable. This review aims to emphasize the importance of bone marrow evaluation in adult patients newly diagnosed with DLBCL and suggest an optimal diagnostic approach to identify bone marrow involvement in these patients.

H syndrome: A histiocytosis-lymphadenopathy plus syndrome. A comprehensive review of the literature.

H syndrome is a rare autosomal recessive genodermatosis that falls under the histiocytosis-lymphadenopathy plus syndrome. The term "H syndrome" includes manifestations such as hyperpigmentation, hypertrichosis, hepatosplenomegaly, heart anomalies, hearing loss, hypogonadism, low height, and occasionally hyperglycemia. The syndrome is associated with mutations in the SLC29A3 gene, which encodes the human equilibrative transporter 3 present in endosomes, lysosomes, and mitochondria. The generalized and ubiquitous presence of affected lysosomes and mitochondria contributes to the systemic and phenotypically heterogeneous manifestations of the syndrome. H syndrome manifestations are cutaneous, systemic, and organ-specific. The pathognomonic signs are hypertrichosis and hyperpigmentation in the inner thighs and shins. However, not all patients present with these symptoms. H syndrome management involves a multidisciplinary approach to address specific symptoms and complications. The prognosis of H syndrome depends on several factors, including the extent and severity of clinical manifestations, the presence of complications, and timely diagnosis and management. Further studies are needed to explore the association between prognosis and the different mutations encountered in H syndrome.

Minimal residual disease testing for classical Hodgkin lymphoma: A comprehensive review.

Classical Hodgkin lymphoma (cHL) is a common lymphoma that affects young patients. Fortunately, the disease is highly curable as it is susceptible to the currently available treatment modalities. Disease monitoring with Positron Emission Tomography and Computed Tomography (PET/ CT) is an integral part of managing these patients. PET guided protocols are currently used to adjust treatment according to the response. The pivotal idea behind the use of response-adapted approaches is to preserve efficacy while decreasing the toxicity. It also helps to intensify therapy in patients in need because of suboptimal response. However, imaging techniques are limited by their sensitivity and specificity. Minimal Residual Disease (MRD) assessment is a newly emerging concept in many hematologic malignancies. It utilizes various molecular techniques such as polymerase chain reaction (PCR), and next-generation sequencing (NGS) as well as flow cytometry, to detect disease traces. This review looks into MRD detection techniques, its current applications, and the evidence in the literature for its use in cHL.

Myeloablative Haploidentical Donor Hematopoietic Transplantation Using Post-Transplantation Cyclophosphamide and Antithymocyte Globulin.

Haploidentical donor (haplo-) hematopoietic stem cell transplantation (HSCT) with post-transplantation cyclophosphamide (PTCy) is now performed on a large scale worldwide. Our patient outcomes did not completely reflect the results published by other groups. We herein present the results of 60 patients with hematologic malignancies treated homogeneously on a modified version of the standard protocol by adding ATG as an additional graft-versus-host disease (GVHD) prophylaxis measure. This was a retrospective analysis of 60 haplo-HSCT recipients using a myeloablative conditioning regimen with antithymocyte globulin and PTCy for GVHD prophylaxis. At 5 years, overall survival was 59.2%, relapse-free survival (RFS) was 48.6%, and chronic GVHD (cGVHD) and relapse-free survival was 40%. The median time to neutrophil and platelet engraftment was 16 days and 28.5 days, respectively. The rates of grade II-IV acute GVHD and extensive cGVHD were 46.7% and 23.3%, respectively. The cumulative incidence of relapse was 30%, nonrelapse mortality was 21.6%, and transplantation-related mortality was 11%. Higher Disease Risk Index and 50% HLA match were associated with lower RFS. Female donor to male recipient and older donor age were associated with an elevated risk of cGVHD. The use of PTCy might not yield the same results in different populations. Many remaining questions need to be addressed in randomized trials, including optimal graft source and donor, date of calcineurin inhibitor initiation, personalized or targeted dose of PTCy, immune reconstitution, and others.

Improved long-term survival rate in the responders to bortezomib, cyclophosphamide, dexamethasone induction therapy in a transplant-eligible cohort of predominantly middle-age multiple myeloma patients.

BACKGROUND: Multiple myeloma (MM) represents the second most common hematologic malignancy (15%). Induction with bortezomib, cyclophosphamide, and dexamthasone VCd (d: low dose dexamthasone) regimen is widely used due to its high effectiveness, low toxicity and good tolerability, particularly with renal impairment. Real-world data on the use of VCD in clinical practice is lacking. OBJECTIVES: Evaluate the real-world experience of the VCD regimen. DESIGN: Retrospective. SETTING: Tumor registry database of tertiary cancer care center. PATIENTS AND METHODS: newly diagnosed MM patients who received VCD induction and underwent autologous stem cell transplant (ASCT) from July 2007 to July 2020. MAIN OUTCOME MEASURES: response evaluation, progression-free survival (PFS) and overall survival (OS). SAMPLE SIZE: 87 patients. RESULTS: Of 102 patients who started induction with VCd, 87 patients experienced a partial response or more overall response rate of 85%). The median age of these 87 patients at diagnosis was 52 years, of which 29.9% presented with renal impairment and 60.3% of patients had stage 2 by the Revised International Staging System (R-ISS). Patients with a standard cytogenetic risk achieved a better response compared to those with a poor cytogenetic risk (P=.044). The post-induction response rates were 6.9% stringent complete remission (sCR), 35% complete remission (CR); 41.4% very good partial response (VGPR), and 16.1% partial response (PR), respectively; the response rates became greater for sCR and CR post-transplantation at day 100 with 16.1% sCR, 35.6% CR, 32.2% VGPR and 16.1% PR, respectively. The median PFS was 49 months and 5 years OS was 84%. PFS was better in patients who achieved sCR vs PR (83 vs 35 months, P=.037). High LDH, high-risk cytogenetic and stage 3 R-ISS showed a worse median PFS and OS. CONCLUSIONS: VCD induction in newly diagnosed MM is highly effective, convenient, tolerable and affordable regimen, especially in low and middle-income countries with limited resources, also with favorable outcomes and survival. while those who did not respond successfully shifted to VRD or VTD. LIMITATIONS: The usual limitations of a retrospective analysis using registry-level data, no data on quality of life.

Non-cryopreserved autologous peripheral blood stem cell transplantation for multiple myeloma and lymphoma in countries with limited resources: practice considerations from the Worldwide Network for Blood and Marrow Transplantation.

Autologous peripheral blood stem cell (PBSC) transplantation is a standard treatment of multiple myeloma (MM), Hodgkin lymphoma and various subtypes of non-Hodgkin lymphoma. Cryopreservation of hematopoietic stem cells is standard practice that allows time for delivery of conditioning regimen prior to cell infusion. The aim of this Worldwide Network for Blood & Marrow Transplantation (WBMT) work was to assess existing evidence on non-cryopreserved autologous transplants through a systematic review/meta-analysis, to study feasibility and safety of this approach. We searched PubMed, Web of Science and SCOPUS for studies that utilized non-cryopreserved autologous PBSC transplantation. Identified literature was reviewed for information on mobilization, apheresis, preservation and viability, conditioning regimen, engraftment, response, and survival. Results highlight collective experience from 19 transplant centers (1686 patients), that performed autologous transplants using non-cryopreserved PBSCs. The mean of infused CD34+ was 5.6 × 106/kg. Stem cell viability at transplantation was >90% in MM and >75% in lymphomas, after a storage time of 24-144 h at +4 °C. Mean time-to-neutrophil engraftment was 12 days and 15.3 days for platelets. Pooled proportion estimates of day 100 transplant-related mortality and graft failure were 1% and 0%, respectively. Non-cryopreservation of apheresed autologous PBSCs appears feasible and safe.

Safety and efficacy of immune checkpoint inhibitors after allogeneic hematopoietic cell transplantation.

The immune system plays a major role in preventing infections and cancers. Impairment in immunity may facilitate the development of neoplasia owing to defective immune surveillance, among other mechanisms. Immune evasion plays a significant role in relapse after allogeneic hematopoietic cell transplantation (alloHCT); one purported mechanism is through immune checkpoint signaling pathways. Checkpoint inhibitors (CPIs) are FDA approved for relapsed classical Hodgkin's Lymphoma (cHL), primary mediastinal large B cell Lymphoma (PMBCL) and other solid tumors. Retrospective studies evaluating the outcomes of alloHCT after prior exposure to CPIs showed favorable survival outcomes but high rates of graft-versus-host disease (GVHD); the risk appears to be lower when using post-transplant cyclophosphamide as GVHD prophylaxis. CPIs have increasingly been used to prevent or treat post-alloHCT relapse. Available data, albeit limited, supports the clinical activity of CPIs in post-alloHCT relapse; however, serious and even fatal cases of GVHD have been reported. The optimal timing, schedule, dosing, and patients likely to benefit from this strategy are yet to be identified. In this review, we highlight the immune system's role in cancer surveillance and relapse prevention and discuss the current clinical evidence of CPIs use in post-alloHCT relapse.

Role of Anti-CD38 Monoclonal Antibodies in the Treatment of Adult Immune Hematological Diseases.

Daratumumab is a first-in-class human anti-CD38 IgG1 monoclonal antibody approved for treating newly diagnosed and relapsed refractory multiple myeloma. Pre-clinical data supported daratumumab's ability to deplete autoantibodies producing plasma cells, B-cells, and NK cells. Those reports showed promising results on using daratumumab in autoimmune disorders that are refractory to multiple lines of therapies, which encouraged using daratumumab in various autoimmune conditions that are refractory to standard therapies. This review aims to summarize the literature reporting experience using anti-CD38 antibodies in hematological autoimmune diseases, focusing on the most common autoimmune hematological diseases, including autoimmune hemolytic anemia, immune thrombocytopenia, post-transplant cytopenia, and pure red blood cell aplasia.

Hematologic Manifestations of Parvovirus B19 Infection.

Parvovirus B19 virus infection is widespread among humans because of its highly infectious and obstinate nature, with up to 80% of the population testing positive for IgG antibodies against the virus. Pronormoblasts observed in biopsy are the hallmarks of PVB19 infection. In addition, PVB19 affects the skin, heart, brain, joints, and liver and can be diagnosed through antibody detection or DNA detection via PCR. Due to its capsid proteins' high affinity for bone marrow receptors, its main presentation is the suppression of bone marrow functions. It has been shown to affect patients with hemolytic anemia and patients with hematological malignancies, presenting with pure red cell aplasia. The main available effective treatment option is IV immunoglobulins; however, the risk of recurrence remains high after treatment.