Hematopoietic stem cell transplant in two pediatric patients testing positive for SARS-CoV-2: A case report.

BACKGROUND: The SARS-CoV-2 pandemic brought challenges to all areas of medicine. In pediatric bone marrow transplant (BMT), one of the biggest challenges was determining how and when to transplant patients infected with SARS-CoV-2 while mitigating the risks of COVID-related complications. METHODS: Our joint adult and pediatric BMT program developed protocols for performing BMT during the pandemic, including guidelines for screening and isolation. For patients who tested positive for SARS-CoV-2, the general recommendation was to delay BMT for at least 14 days from the start of infection and until symptoms improved and the patient twice tested negative by polymerase chain reaction (PCR). However, delaying BMT in patients with malignancy increases the risk of relapse. RESULTS: We opted to transplant two SARS-CoV-2 persistently PCR positive patients with leukemia at high risk of relapse. One patient passed away early post-BMT of a transplant-related complication. The other patient is currently in remission and doing well. CONCLUSION: These cases demonstrate that when the risk associated with delaying BMT is high, it may be reasonable to proceed to transplant in pediatric leukemia patients infected with SARS-CoV-2.

How I treat cryoglobulinemia.

Cryoglobulinemia is a distinct entity characterized by the presence of cryoglobulins in the serum. Cryoglobulins differ in their composition, which has an impact on the clinical presentation and the underlying disease that triggers cryoglobulin formation. Cryoglobulinemia is categorized into two main subgroups: type I, which is seen exclusively in clonal hematologic diseases, and type II/III, which is called mixed cryoglobulinemia and is seen in hepatitis C virus infection and systemic diseases such as B-cell lineage hematologic malignancies and connective tissue disorders. Clinical presentation is broad and varies between types but includes arthralgia, purpura, skin ulcers, glomerulonephritis, and peripheral neuropathy. Life-threatening manifestations can develop in a small proportion of patients. A full evaluation for the underlying cause is required, because each type requires a different kind of treatment, which should be tailored on the basis of disease severity, underlying disease, and prior therapies. Relapses can be frequent and can result in significant morbidity and cumulative organ impairment. We explore the spectrum of this heterogeneous disease by discussing the disease characteristics of 5 different patients.

Circulating microfilariae in haematological malignancies: do they have a role in pathogenesis?

Filariasis is very common in tropical countries. It is endemic in the coastal areas of India. We report four cases of haematological malignancy where peripheral blood and bone marrow smears did not show any microfilariae but conventional cytogenetic preparations from all the four cases showed the presence of parasites. Their morphology confirmed the diagnosis of all cases as bancroftian filariasis. Therefore all types of cytogenetic preparations should be screened carefully in the endemic areas along the coastal zones of India for the presence of this parasite.

Reduced-Intensity Conditioning with Fludarabine, Cyclophosphamide, and Rituximab Is Associated with Improved Outcomes Compared with Fludarabine and Busulfan after Allogeneic Stem Cell Transplantation for B Cell Malignancies.

Reduced-intensity conditioning (RIC) has been used increasingly for allogeneic hematopoietic cell transplantation to minimize transplant-related mortality while maintaining the graft-versus-tumor effect. In B cell lymphoid malignancies, reduced-intensity regimens containing rituximab, an antiCD20 antibody, have been associated with favorable survival; however, the long-term outcomes of rituximab-containing versus nonrituximab-containing regimens for allogeneic hematopoietic cell transplantation in B cell lymphoid malignancies remain to be determined. We retrospectively analyzed 94 patients who received an allogeneic transplant for a B cell lymphoid malignancy. Of these, 33 received RIC with fludarabine, cyclophosphamide, and rituximab (FCR) and graft-versus-host disease (GVHD) prophylaxis with a calcineurin inhibitor and mini-methotrexate, and 61 received RIC with fludarabine and busulfan (FluBu) and GVHD prophylaxis with a calcineurin inhibitor and mycophenolate mofetil. The 2-year overall survival was superior in patients who received FCR versus FluBu (72.7% versus 54.1%, P = .031), and in multivariable analysis adjusted for Disease Risk Index and donor type, only the conditioning regimen (FluBu versus FCR: HR, 2.06; 95% CI, 1.04 to 4.08; P = .037) and Disease Risk Index (low versus intermediate/high: HR, .38; 95% CI, .17 to .86; P = .02) were independent predictors of overall survival. The 2-year cumulative incidence of chronic GVHD was lower in patients who received FCR versus FluBu (24.2% versus 51.7%, P = .01). There was no difference in rate of relapse/progression or acute GVHD. Our results demonstrate that the use of RIC with FCR and GVHD prophylaxis with a calcineurin inhibitor and mini-methotrexate is associated with decreased chronic GVHD and improved overall survival.

Leukemia cutis in a patient of relapsed leprosy- Coincidence or predisposition?

Leprosy, a disease of skin and peripheral nerves has varied manifestations which principally affect the immune status of the host. Leukemic skin infiltrations in patients with leukemia are referred to as leukemia cutis. It can be seen in all types of leukemia, especially in patients with acute myelomonocytic leukemia (AML). In majority of cases, the cutaneous lesions are nonspecific manifestations associated with an impaired immune system.1 Though various malignancies have been documented with leprosy, no case of borderline-tuberculoid (BT) Hansen's disease with coexisting leukemia cutis has ever been reported in literature to the best of our knowledge.

Polyclonal gammopathy after BKV infection in HSCT recipient: a novel trigger for plasma cells replication?

BACKGROUND: BK polyomavirus infects most of the general population. However, its clinical manifestations are almost exclusively seen in immunocompromised patients, particularly in kidney and hematopoietic stem cell transplantation recipients. CASE PRESENTATION: A 15-y-old female suffering from common B-cell acute lymphoblastic leukaemia underwent hematopoietic stem cell transplantation. The patient had reactivation of BKPyV infection and developed an haemorrhagic cystitis. Three months after transplant, BKPyV viremia and viruria increased and she developed a severe nephropathy associated to a polyclonal gammopathy with high levels of isolated IgM. CONCLUSION: This case report describes a rare and unexpected polyclonal gammopathy developed during a polyomavirus-associated nephropathy confirmed by immunohistochemical and laboratory analyses.

Myelopathy following intrathecal chemotherapy in adults: a single institution experience.

Methotrexate and cytarabine arabinoside are frequently administered intrathecally in the prophylaxis and treatment of patients with hematological malignancies. Myelopathy as a complication of intrathecal (IT) chemotherapy is rare in adults, with most of the cases described in the literature occurring in the pediatric population. Between January 2010 and March 2014, 587 newly diagnosed B cell acute lymphoblastic leukemia and 24 chronic myeloid leukemia lymphoid blast phase patients were seen at The University of Texas MD Anderson Cancer Center. This case series discusses seven adult cases deemed to have IT chemotherapy-induced myelopathy between 2010 and 2014 at MD Anderson Cancer Center. Five out of the seven patients had T2 abnormalities involving the dorsal columns of the spinal cord. An elevated myelin basic protein level was noted in the two patients in whom it was checked. The wide range of dosage and timing with respect to IT chemotherapy administration suggests an idiosyncratic reaction or individual threshold to the development of myelopathy. By describing the largest case series of myelopathy in adults, we aim to raise awareness about this rare albeit devastating complication. Based on the seven cases described we would recommend-MRI of the spine with T2-weighted imaging in the sagittal and axial planes in leukemia patients with unexplained myelopathy and consideration to delay IT chemotherapy until after an extensive work-up to rule out CNS leukemia. Though more data are needed on the use of folate metabolites, preliminary results have shown some promise in the treatment of methotrexate-induced myelopathy and may be a potential consideration for future patients suspected to have chemotherapy induced myelopathy.

No evidence of Polyomavirus and EBV infections in Italian patients with mixed cryoglobulinemia infected chronically with HCV.

Mixed cryoglobulinemia is a lymphoproliferative disorder associated with hepatitis C virus (HCV). In patients chronically affected by HCV the prevalence of mixed cryoglobulinemia is variable ranging from 0% to 56%. To verify whether polyomaviruses (PyV) play a role in this disorder a total of 222 blood samples from 63 HCV chronic patients, 43 with mixed cryoglobulinemia, 59 chronic lymphocytic leukemia, 50 polytransfused patients, and 50 blood donors were evaluated for Merkel (MCPyV), BKV, JCV, and SV40. EBV was additionally included in the analysis since association with this disorder has been reported. Mixed cryoglobulinemia patients infected chronically with HCV resulted negative for both PyV and EBV. MCPyV was found in 1 subject with Merkel Cell Carcinoma, in 10% of polytransfused and in 10% of blood donors while EBV was detected in 22% of polytransfused, 10% of B-cell lymphatic leukemia patients and 4% of blood donors (P < 0.01). Taken together, the absence of PyV and EBV in HCV-mixed cryoglobulinemia patients seems to exclude a direct involvement of these viruses in the pathogenesis of this disease while the presence of MCPyV in healthy individuals, at the same rate as in polytransfused patients, may reinforce data on a minimal role of this virus in other human pathologies.

Liver transplantation in an adolescent with acute liver failure from acute lymphoblastic leukemia.

The most common identifiable causes of acute liver failure in pediatric patients are infection, drug toxicity, metabolic disease, and autoimmune processes. In many cases, the etiology of acute liver failure cannot be determined. Acute leukemia is an extremely rare cause of acute liver failure, and liver transplantation has traditionally been contraindicated in this setting. We report a case of acute liver failure in a previously healthy 15-yr-old male from pre-B-cell acute lymphoblastic leukemia. He underwent liver transplantation before the diagnosis was established, and has subsequently received chemotherapy for pre-B-cell acute lymphoblastic leukemia. He is currently alive 31 months post-transplantation. The published literature describing acute lymphoblastic leukemia as a cause of acute liver failure is reviewed.

Nephrotic syndrome associated with tyrosine kinase inhibitors for pediatric malignancy: case series and review of the literature.

BACKGROUND: Tyrosine kinase (TK) inhibitors are increasingly being used to treat a variety of pediatric malignancies. Reports in adult patients describe a range of effects of TK inhibitors on the kidney, including hypertension, proteinuria, acute kidney injury, and thrombotic microangiopathy (TMA); however, there are only a few reports of TK-inhibitor-associated nephrotic syndrome. METHODS: We report four pediatric patients with various malignancies (chronic myelogenous leukemia, acute lymphoblastic leukemia, and glioma/renal cell carcinoma) who developed nephrotic syndrome during treatment with TK inhibitors (imatinib, sunitinib, dasatinib, and quizartinib). One of the four patients also had clinical features of TMA. RESULTS: Three of the four patients achieved complete remission of nephrotic syndrome with discontinuation of the TK inhibitor and have had no additional nephrotic syndrome relapses to date. The temporal relationship of nephrotic syndrome onset to TK-inhibitor therapy and resolution of nephrotic syndrome with cessation of therapy strongly imply an association in these patients. CONCLUSIONS: TK inhibitors are important therapies in pediatric cancer, and their use is expanding. Nephrotic syndrome with or without features of TMA is a potential complication of these therapies in children.

Myelopathy mimicking subacute combined degeneration in a Down syndrome patient with methotrexate treatment for B lymphoblastic leukemia: report of an autopsy case.

We report clinicopathological features of a 23-year-old woman with Down syndrome (DS) presenting with subacute myelopathy treated with chemotherapy, including intravenous and intrathecal administration of methotrexate (MTX), and with allogenic bone-marrow transplantation for B lymphoblastic leukemia. Autopsy revealed severe demyelinating vacuolar myelopathy in the posterior and lateral columns of the spinal cord, associated with macrophage infiltration, marked axonal loss and some swollen axons. Pathological changes of posterior and lateral columns were observed from the medulla oblongata to lumbar cord. Proximal anterior and posterior roots were preserved. Cerebral white matter was relatively well preserved. There were no vascular lesions or meningeal dissemination of leukemia. Longitudinal extension of cord lesions was extensive, unlike typical cases of subacute combined degeneration (SACD), but distribution of lesions and histological findings were similar to that of SACD. DS patients show heightened sensitivity to MTX because of their genetic background. Risk factors for toxic myelopathy of DS are discussed, including delayed clearance of MTX despite normal renal function, alterations in MTX polyglutamation and enhanced folic acid depletion due to gene dosage effects of chromosome 21. Alteration of folate metabolism and/or vitamin B12 levels through intravenous or intrathecal administration of MTX might exist, although vitamin B12 and other essential nutrients were managed using intravenous hyperalimentation. To the best of our knowledge, this is the first report of an autopsy case that shows myelopathy mimicking SACD in a DS patient accompanied by B lymphoblastic leukemia. The case suggests a pathophysiological mechanism of MTX-related myelopathy in DS patients with B lymphoblastic leukemia mimicking SACD.

Hyper-eosinophilia in granular acute B-cell lymphoblastic leukemia with myeloid antigen expression.

Acute lymphoblastic leukemia with eosinophilia (ALLEo) is a rare but a distinctive clinical entity. Clinical features of idiopathic hyper-eosinophilic syndrome (HES) can be seen in patients with ALLEo. We report a 10-year-old girl, in whom HES was initially suspected but further investigation confirmed the diagnosis of acute B-cell lymphoblastic leukemia with myeloid antigen expression. Clinical response to chemotherapy was excellent with achievement of complete remission for 4 years. Serum interleukin-3 and -5 were elevated at presentation and normalized with disappearance of eosinophilia after induction therapy, supporting the reactive nature of eosinophilia in ALLEo. Hematologic malignancy should be considered in patients with hyper-eosinophilia, before attributing it to HES.

Leser-Trélat sign presenting in a patient with recurrent pre-B-cell acute lymphocytic leukemia.

The presence of multiple seborrheic keratoses appearing abruptly in association with an underlying malignancy is known as Leser-Trélat sign, a rare paraneoplastic cutaneous syndrome. Although this finding is most commonly associated with solid organ tumors, it also can be a clue for the presence of underlying hematologic malignancies. We present a unique case of Leser-Trélat sign in a 20-year-old man who experienced a relapse of pre-B-cell acute lymphocytic leukemia (ALL) that was previously treated with multiple courses of chemotherapy and external radiation therapy. The patient was admitted for a new cycle of chemotherapy with etoposide and cyclophosphamide and was noted to have an eruption of yellowish brown papules and plaques over his upper body. Biopsy of a representative lesion was consistent with seborrheic keratosis. A large number of rapidly appearing seborrheic keratoses is an uncommon finding in young patients and should be considered clinically suspicious as a potential indicator of Leser-Trélat sign. A thorough history and physical examination should be performed in patients presenting with this sign to rule out possible internal solid organ and hematologic malignancies.

[A retrospective comparative study of haplotype hematopoietic stem cell transplantation and human leukocyte antigen-matched sibling donor hematopoietic stem cell transplantation in the treatment of acute B-lymphocyte leukemia].

Objective: To investigate whether haplotype hematopoietic stem cell transplantation (haplo-HSCT) is effective in the treatment of pre transplant minimal residual disease (Pre-MRD) positive acute B lymphoblastic leukemia (B-ALL) compared with HLA- matched sibling donor transplantation (MSDT) . Methods: A total of 998 patients with B-ALL in complete remission pre-HSCT who either received haplo-HSCT (n=788) or underwent MSDT (n=210) were retrospectively analyzed. The pre-transplantation leukemia burden was evaluated according to Pre-MRD determinedusing multiparameter flow cytometry (MFC) . Results: Of these patients, 997 (99.9% ) achieved sustained, full donor chimerism. The 100-day cumulative incidences of neutrophil engraftment, platelet engraftment, and grades Ⅱ-Ⅳ acute graft-versus-host disease (GVHD) were 99.9% (997/998) , 95.3% (951/998) , and 26.6% (95% CI 23.8% -29.4% ) , respectively. The 3-year cumulative incidence of total chronic GVHD was 49.1% (95% CI 45.7% -52.4% ) . The 3-year cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) of the 998 cases were 17.3% (95% CI 15.0% -19.7% ) and 13.8% (95% CI 11.6% -16.0% ) , respectively. The 3-year probabilities of leukemia-free survival (LFS) and overall survival (OS) were 69.1% (95% CI 66.1% -72.1% ) and 73.0% (95% CI 70.2% -75.8% ) , respectively. In the total patient group, cases with positive Pre-MRD (n=282) experienced significantly higher CIR than that of subjects with negative Pre-MRD [n=716, 31.6% (95% CI 25.8% -37.5% ) vs 14.3% (95% CI 11.4% -17.2% ) , P<0.001]. For patients in the positive Pre-MRD subgroup, cases treated with haplo-HSCT (n=219) had a lower 3-year CIR than that of cases who underwent MSDT [n=63, 27.2% (95% CI 21.0% -33.4% ) vs 47.0% (95% CI 33.8% -60.2% ) , P=0.002]. The total 998 cases were classified as five subgroups, including cases with negative Pre-MRD group (n=716) , cases with Pre-MRD<0.01% group (n=46) , cases with Pre-MRD 0.01% -<0.1% group (n=117) , cases with Pre-MRD 0.1% -<1% group (n=87) , and cases with Pre-MRD≥1% group (n=32) . For subjects in the Pre-MRD<0.01% group, haplo-HSCT (n=40) had a lower CIR than that of MSDT [n=6, 10.0% (95% CI 0.4% -19.6% ) vs 32.3% (95% CI 0% -69.9% ) , P=0.017]. For patients in the Pre-MRD 0.01% -<0.1% group, haplo-HSCT (n=81) also had a lower 3-year CIR than that of MSDT [n=36, 20.4% (95% CI 10.4% -30.4% ) vs 47.0% (95% CI 29.2% -64.8% ) , P=0.004]. In the other three subgroups, the 3-year CIR was comparable between patients who underwent haplo-HSCT and those received MSDT. A subgroup analysis of patients with Pre-MRD<0.1% (n=163) was performed, the results showed that cases received haplo-HSCT (n=121) experienced lower 3-year CIR [16.0% (95% CI 9.4% -22.7% ) vs 40.5% (95% CI 25.2% -55.8% ) , P<0.001], better 3-year LFS [78.2% (95% CI 70.6% -85.8% ) vs 47.6% (95% CI 32.2% -63.0% ) , P<0.001] and OS [80.5% (95% CI 73.1% -87.9% ) vs 54.6% (95% CI 39.2% -70.0% ) , P<0.001] than those of MSDT (n=42) , but comparable in 3-year NRM [5.8% (95% CI 1.6% -10.0% ) vs 11.9% (95% CI 2.0% -21.8% ) , P=0.188]. Multivariate analysis showed that haplo-HSCT was associated with lower CIR (HR=0.248, 95% CI 0.131-0.472, P<0.001) , and superior LFS (HR=0.275, 95% CI 0.157-0.483, P<0.001) and OS (HR=0.286, 95% CI 0.159-0.513, P<0.001) . Conclusion: Haplo HSCT has a survival advantage over MSDT in the treatment of B-ALL patients with pre MRD<0.1% .

B cell acute lymphocytic leukemia in pregnancy.

Acute lymphocytic leukemia (ALL) is a rare occurrence in pregnancy and can be rapidly fatal if left untreated. The need for immediate treatment of ALL, coupled with the maternal-fetal risks from the chemotherapy regimen render a therapeutic dilemma in pregnant women with ALL. We report a case of ALL diagnosed in the 24th week of pregnancy to outline our management strategy, to demonstrate the feasibility of treatment with multi-agent chemotherapy, and to provide a review of the literature.