Nitin Sood

Picking up myelodysplastic syndromes and megaloblastic anemias on peripheral blood: use of NEUT-X and NEUT-Y in guiding smear reviews.

Sir, Diagnosing myelodysplastic syndrome (MDS) poses a peculiar challenge as they mainly present as cytopenia(s), which can occur due to a myriad of hematological and nonhematological factors. On a routine complete blood count (CBC) flagged for cytopenia(s), evaluating neutrophilic dysplasia on light microscopy suffers from a multitude of problems such as pH of the stain, quality of staining, time gap in preparation of smear, interobserver variation, and morphological alterations encountered due to secondary causes such as drugs, nutritional, toxin. There is no single parameter or test available to diagnose MDS, and so an extensive workup is required. Apart from battery of tests required, there are other morphologic overlaps present which may further complicate the problem such as megaloblastic anemia (MA) and few subtypes of myeloproliferative neoplasm (MPN). MA cases can present with pancytopenic blood picture with dyspoiesis noted in one or more lineages, similar to that noted in early MDS patients, making the early diagnosis of MDS cases difficult. The macrocytosis in MA can be obscured by concomitant disorders that in themselves cause microcytosis although the leukocyte abnormalities are preserved, resulting in masked MA [1]. Another differential of macrocytosis is MDS, which can be suspected by the presence of hypogranular neutrophils and monocytosis. Thus, in such cases, peripheral smear alone is not of much help, and further invasive tests such as bone marrow examination and cytogenetics needs to be carried out. MPN, on the other hand, usually can be differentiated from MDS and MA cases morphologically, however, with few overlaps, as in cases of primary myelofibrosis in fibrotic phase, MDS/MPN group which includes chronic myelomonocytic leukemia (CMML), atypical CML, juvenile myelomonocytic leukemia, and MDS/MPNU. They may have some clinical, laboratory, or morphologic findings at the time of initial presentation that support a diagnosis of MDS more than MPN. One or more of the other lineages may exhibit ineffective proliferation so that such cases may present with cytopenia(s) as well [2]. Such cases can present as a challenge and need to be differentiated from early cases of MDS. Neutrophil dysplasia is a feature seen in MDS as well as in CMML, thus making it difficult for NEUT-X and NEUT-Y values to differentiate them [3]. As MA is also associated with structural abnormalities in RBC and WBC as seen in MDS, they were also included in the study to evaluate its possible role in NEUT-X and NEUT-Y We evaluated the role of parameters NEUT-X and NEUT-Y (Sysmex XE-2100; Sysmex corporation, Kobe, Japan) in detecting neutrophil dysplasia in suspected MDS, MA, and MPN cases. NEUT-X and NEUT-Y are the latest parameters for neutrophil structural and maturation, NEUT-X is the direct measurement of side scatter diffraction, corresponding to channel number, and is representative of the internal structure of the neutrophils. It correlates with hypogranularity of neutrophils and when taken into consideration with anemia is suggestive of an underlying MDS. NEUT-Y is the direct measurement of the fluorescence intensity [1]. This study included four groups: control, MDS, MPN, and MA group with the aim to compare the NEUT-X and NEUT-Y values among each group as well as to record whether these two parameters have any relationship between each other in individual groups. The control group includes 66 cases which came for routine check up with no complaints or comorbidities, 30 cases diagnosed as MDS, 56 cases of MPN, and 16 cases of MA. The cases were collected over a period of one and a half years (March 2012–August 2013). Inclusion criteria in the study were as follows: • All the cases were diagnosed using multiparametric approach

Newly established stem cell transplant program: 100 days follow-up of patients and its comparison with published Indian literature

Background: Hematopoietic progenitor stem cell transplantation (HPSCT) is used as a standard treatment option to improve outcome in hematological and nonhematological disorders. It is important for new HPSCT program to look at its patient outcome data and compare it with the published data to evaluate the efficacy of program. Aims: The aim was to compile and collate the patient outcome data of HPSCT and compare with published reports. Materials and Methods: Patient demographics, indications, stem cell harvest by apheresis, dose collected, infusion, engraftment, and follow-up data were collected from hospital information system from 2010 to 2013 in a tertiary care hospital. HPSCs were mobilized with granulocyte colony-stimulating factor, and harvests were done on the 5th day. Engraftment was decided for neutrophil when counts were 0.5 × 109/L and for platelets when counts were 20 × 109/L on two consecutive days without any transfusion support. Results: There were 133 harvests for 95 patients with various disorders; multiple myeloma was most common in autologous and acute lymphoblastic leukemia in allogeneic group. One hundred harvests were done for autologous and 33 for allogeneic HPSCT. In autologous group, of 66 patients, 60 (90.9%) received stem cell infusion at median dose of 4.63 × 106 CD34+ cells/kg. Similarly, in allogeneic group, of 29 patients, 27 (93.10%) received infusion at median dose of 5.8 × 106 CD34+ cells/kg. 58 (96.9%) patients and 25 (92.6%) engrafted in autologous and allogeneic group, respectively. The median time for neutrophils engraftment was 11 days in autologous group and 12 days in allogeneic group. The median time for platelet engraftment was 11.5 days in autologous group and 13 days in allogeneic group. The 100-day survival rate was 95% (n = 57) in autologous group and 77.8% (n = 21) in allogeneic group. Conclusion: This data analysis shows reasonably good results of HPSCTs with majority of patients surviving at 100-day follow-up.

Synchronous Nodal involvement by Metastatic Adenocarcinoma and Classical Hodgkin's Lymphoma

The cervical lymph nodes (LNs), along with being the primary site of lymphomas, are also the draining sites for malignancies of the gastrointestinal tract, breasts, lungs, etc. Hodgkin’s disease also most commonly affects the cervical and axillary LNs. We, in the era of modern techniques for diagnosing malignancies, stress the fact that a diligent histopathological examination of the background lymphoid tissue is important to exclude a coexistent lymphoma, particularly after a metastasis is found.

Total leukocyte count-based predictor tool for calculating hematopoietic progenitor cell dose in bone-marrow harvest

Background: Hematopoietic progenitor cell transplantation is increasingly being used as the curative therapy in India for various clinical conditions. There are three main sources of hematopoietic progenitor cells; hematopoietic progenitor cell-apheresis (HPC-A), hematopoietic progenitor cell-bone marrow (HPC-M) and hematopoietic progenitor cell-Umbilical Cord (HPC-C). The number of CD34+ cells in HPC-C is fixed. In HPC-A, the number of CD34+ cells collected is based on the baseline peripheral blood counts and a second harvest can be easily performed. The trickiest calculation of CD34+ cells adequacy is in case of HPC-M harvest, where the end point of harvest cannot be predetermined. Aim: The aim was to study the accuracy of a total leukocyte count (TLC)-based predictor tool in predicting CD34+ dose in comparison to the actual CD34+ cell counts in the harvest. Materials and Methods: This was a prospective study to validate the tool. The data captured included patient and donor demographic data, disease condition, mobilization regimen of the donor, progenitor cell harvest data, dose collected, cryopreservation if any, progenitor cell infusion data, engraftment, and follow-up of the patient including day thirty and day hundred chimerism in a tertiary care hospital. Results: Five patients were included in the study. For each patient, the target dose and volume were collected in a single HPC-M harvest attempt, and no repeat harvests were required. The average volume of HPC-M harvest collected was 195 ml. The average CD-34+ cell dose in HPC-M harvest achieved was 4.3 × 106/kg (Range = 3.39–6.42). This was 85.7% of the targeted dose calculated on the basis of TLC-based predictor tool. Conclusion: This study reiterates the importance of a simple TLC-based predictor tool (formula) for estimation of HPC-M volume to be harvested.

Intracytoplasmic inclusions in plasma cells: A diagnostic adjunct in monoclonal gammopathy of undetermined significance

Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant plasma cell (PC) disorder characterized by the presence of monoclonal (M) protein in the blood, less than the myeloma level without any features of end‐organ damage (lytic bone lesions, anemia, hypercalcemia, renal insufficiency, and hyperviscosity). Bone marrow (BM) PCs are usually <10% in MGUS. Changes in the cell nucleus as an increase in size, irregular shape, diffuse chromatin pattern, and the presence of nucleoli along with cytoplasmic contour irregularities and anisocytosis in PCs are markers of abnormal PCs and can be used to cytomorphologically differentiate this from reactive plasmacytosis.[1] Auer rod‐like/crystalline intracytoplasmic inclusions in PCs are described rarely in multiple myeloma (MM).[2] Other conditions associated with intracytoplasmic inclusions are plasmacytoma, chronic lymphocytic leukemia, lymphoplasmacytic lymphoma, mucosa‐associated lymphoid tissue lymphomas and rarely, high‐grade lymphomas.[3] Although very rarely Auer rod‐like PC inclusions were described in reactive plasmacytosis in a patient of aplastic anemia[4] and acute myeloid leukemia,[5] its presence surely warrant further evaluation in the direction of PC dyscrasia for prompt diagnosis. We report a case of MGUS having 3% PCs in BM aspirate with the presence of multiple discrete azurophilic intracytoplasmic inclusions.

Efficacy and safety of ibrutinib in indian patients with relapsed or refractory chronic lymphocytic leukemia and mantle cell lymphoma: Cases from a named patient program

Context: This named patient program evaluated the safety and efficacy of ibrutinib, a selective inhibitor of Brutons tyrosine kinase in Indian patients with relapsed/refractory chronic lymphocytic leukemia (CLL, with/without chromosome 17 deletion [del17p]) and mantle cell lymphoma (MCL). Subjects and Methods: The eight enrolled patients (relapsed/refractory CLL: n = 6 [4/6 patients with del17p] and relapsed/refractory MCL: n = 2) had median age of 55 years (range, 52–60) and had received a median of 3 (CLL patients) and 4 (MCL patients) prior therapies. Patients received once-daily dose of ibrutinib (420 mg: CLL, 560 mg: MCL). Results: In CLL patients, the median time to response was 3 months (range, 0.5–7) and five of six patients had partial response (PR) whereas one achieved complete response (CR). Median time on treatment was 11.5 months (range, 8–14); five patients continued treatment and one was recommended stem cell transplantation (SCT). Of the two MCL patients, one achieved PR and one showed CR and advanced to SCT. In CLL patients, the median (range) hemoglobin level improved from 9.8 g/dL (7.2–11) at baseline to 12.0 g/dL (9.5–13.2) and median (range) platelet count improved from 150,000 cells/μL (21,000–195,000) at baseline to 190,350 cells/μL (130,000–394,000) at the time of analysis (July 2016). Most adverse events (AEs) reported were infections (n = 2). No Grade 3-4 or serious AEs, dose reductions, or treatment discontinuation due to AEs were reported. Conclusions: In this first real-world experience in Indian patients, ibrutinib demonstrated therapeutic efficacy in relapsed/refractory CLL (with/without del17p) and MCL. Safety results were consistent with the current known profile of ibrutinib.

Hodgkin lymphoma in a case of chronic myeloid leukemia treated with tyrosine kinase inhibitors

Chronic myeloid leukemia (CML) is characterized by increased and unregulated proliferation of granulocytic lineage in the bone marrow and presence of these immature myeloid cells in the peripheral blood with presence of Philadelphia (Ph) chromosome. Tyrosine kinase inhibitors are the most important drugs in the CML therapy and provide long disease-free survival. Due to the increased survival of CML patients with continual administration of these drugs, the chance of development of secondary malignancies may increase. The most common secondary malignancies are prostate, colorectal and lung cancer, non-Hodgkin lymphoma, malignant melanoma, non-melanoma skin tumors and breast cancer. Herein, we are describing a rare case of Hodgkin lymphoma in a patient of CML after ten year of primary disease presentation. Hodgkin lymphoma in a known case of CML is very rare and further studies are also needed to know the pathogenic relationship between the two entities and to assess the risk of secondary Hodgkin lymphoma in CML patients treated with tyrosine kinase inhibitors. CML itself is a risk factor for development of solid cancers and hematologic malignancies. In addition, patients on chemotherapy are immune-compromised and may be at greater risk of neoplasm driven by infectious agents such as Epstein-Barr virus.

Bilateral Tonsillar Enlargement as a First Manifestation of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma with an Unusual Interfollicular Pattern of Infiltration

Tonsillar lymphoma usually presents as unilateral or bilateral enlargement or as an ulcerative or fungating lesions. Most lymphomas that involve the tonsils are diffuse large B-cell lymphomas and primary low grade lymphomas are exceptional. We report a case of primary B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) affecting tonsils with interfollicular pattern of infiltration in a 54-year-old female who clinically presented with bilateral tonsillar enlargement, sore throat, dysphagia and respiratory difficulty, unresponsive to the conservative treatment. To the best of our knowledge, till date only six cases of CLL/SLL infiltrating tonsils have been reported in the English literature, three of these were known cases of CLL/SLL prior to tonsillectomy. In the present case diagnosis of CLL/SLL was first time established on tonsillar histomorphology and that too with an unusual interfollicular pattern of infiltration.

Myelodysplastic syndromes: Where do we stand?

Myelodysplastic syndromes (MDS) are fairly common hematological disorder of elderly. They are a group of clonal malignant hematopoietic stem cell disorders characterized by dysplastic morphology, variable cytopenia and a variable threat of transformation to AML. These dysplastic changes are a result of chromosomal abnormalities and somatic mutations. MDS is the most common myeloid neoplasm of the older adults with median age at diagnosis being 72 years and an average incidence rate of 0.2 per 100,000 people per year. MDS is diagnosed and classified according to the WHO 2008 classification system, which utilizes peripheral blood and bone marrow findings. Other essential investigations include flow cytometry, genetic profile and chromosomal analysis. Various prognostic scoring system have been developed which help guide the treatment. Treatment of complications associated with MDS also forms an essential component of the management of this disease.

Synchronous Diffuse Large B-Cell Lymphoma and Malignant Clonal Plasma Cells in Bone Marrow As Primary Presentation: A Diagnostic and Therapeutic Challenge

Coexistence of Diffuse Large B-Cell Lymphoma (DLBCL) with other morphologically and phenotypically distinct lymphoid neoplasm although unusual, has been reported in literature. The most common lymphoid neoplasms associated with DLBCL are Hodgkins lymphoma, mantle cell lymphoma and marginal zone lymphoma. However, they have been reported predominantly in the sites other than the bone marrow. Rarely, DLBCL associated with paraproteinemia of IgM type, result of monoclonal plasma cell proliferation, has also been reported in literature. There is either an associated increase in the free light chain levels or disruption in the normal kappa: lambda ratio. However, co-existence of DLBCL with malignant non secretory clonal plasma cells, diagnosed primarily in the bone marrow has not been reported in the literature.