ATG-Thymoglobulin Versus ATG-Fresenius for Conditioning in Thalassemia Patients Who Underwent Allogenic Stem Cell Transplantation from Matched-Sibling Donor: A Tertiary Cancer Care Center Short-Term Experience.

Graft rejection and Graft-versus-host disease (GVHD) are some of the significant factors resulting in morbidity and mortality following allogeneic hematopoietic cell transplantation. Prophylaxis for GVHD using T-cell depleting agents is helpful in reducing the transplant-related mortality and graft rejection. Both tATG and fATG exhibit varied amounts of antibody specificities and perform distinct immunomodulatory effects, regardless of their capacity to deplete T-lymphocytes. We conducted this single-center, retrospective study at our center to compare both formulations. Twenty-six patients were included in the study, 13 in each cohort. The median age at diagnosis of ß-thalassemia was 5 months (range, 3-12 months) in the tATG group and 6 months (range, 3-9 months) in the f-ATG group, respectively. Acute GVHD was observed in 1 (7.7) and 2(15.4) in the tATG and fATG group, respectively. No cases of chronic GVHD were observed in either group. There was no difference in the mixed chimerism observed at 6 months in both groups, tATG (n = 5, 38.5%) and fATG (n = 6, 46.15). There was 1 (7.6) rejection at day +72 observed in the tATG group, whereas no rejection was observed in the fATG group. At a mean follow-up duration of 288 days since transplant, there were no deaths in either of the groups. In conclusion, both ATG preparations showed equivalent effectiveness in preventing rejections and GVHD. However, further larger studies are required to establish the long-term efficacy and safety of both formulations in ASCT.

Busulfan and cyclophosphamide-based conditioning regimen still holds the promise of being a safe and efficacious regimen for allogeneic transplantation in patients with transfusion-dependent thalassemia, even in high risk.

Busulfan and cyclophosphamide (BuCy)-based regimen has been used as a standard myeloablative chemotherapy for haematopoietic stem cell transplantation in thalassemia. However, treosulfan-based conditioning regimen has emerged due to concerns of toxicities. We retrospectively analysed the safety and efficacy of fludrabine/Bu/Cy/antithymocyte globulin (ATG) versus treosulfan/thiotepa/fludrabine regimens for Hematopoietic Stem Cell Transplant (HSCT) in transfusion-dependent thalassemia (TDT) conducted at our institute (2013-2021). In 75 patients, 36 (48%) received Flu/Bu/Cy/ATG whereas 39 (52%) received Treo/Thio/Flu. Median age was 6 (1-12) and 9 (1-15) years, respectively. Number of patients with Classes I, II, and III were 14, 10, and 12 in Flu/Bu/Cy/ATG versus 2, 19, and 18 in Treo/Thio/Flu group, respectively. Graft was growth factor mobilized bone marrow in Flu/Bu/Cy/ATG versus peripheral blood stem cell in Treo/Thio/Flu group. Mean stem cell dose was 3.82 (2.2-9.1) versus 5 (1.65-8.01) 106 /kg in Flu/Bu/Cy/ATG versus Treo/Thio/Flu group, respectively. Neutrophils and platelets engrafted at a median of 16 (14-21) and 16 (9-47) days in Flu/Bu/Cy/ATG and 15 (10-20) and 13 (9-41) days in Treo/Thio/Flu group. Median duration of follow-up was 28 (23-32.9) months. Five (6.6%) patients had rejection (all secondary). Venoocclusive disease was observed in 2 (5.7%) versus 4 (10.3%) patients (p = .047), respectively. Flu/Bu/Cy/ATG had 4 (11.4%) patients with acute GVHD versus 15 (38.5%) patients which had significant impact on survival (p = .038). We observed chronic GVHD in 4 (11.4%) and 11 (28.2%) patients, respectively, with significant impact on survival (p = .031). Four (5.1%) patients had TRM in Treo/Thio/Flu group, in contrast to none in Flu/Bu/Cy/ATG group. Mixed chimerism was common in Flu/Bu/Cy/ATG {20 (57.1%)} versus Treo/Thio/Flu group {12 (30.1%)}. Five-year Event Free Survival (EFS) and OS of entire cohort were 87% + 4% and 94% + 3%, respectively. Estimated TFS, EFS, OS of Flu/Bu/Cy/ATG versus Treo/Thio/Flu was 97.1% + 2.9% versus 89.2% + 5.1% (p = .251), 97 + 3% versus 80.7 + 6% (p = .041) and 100% versus 90.4 + 5% (p = .067), respectively. In our experience, Flu/Bu/Cy/ATG regimen is safe and effective even in high-risk TDT. However, one needs to be vigilant for mixed chimerism.

Comparison of CRP and procalcitonin for etiological diagnosis of fever during febrile neutropenia in hematology patients- an experience from a tertiary care center in Northern India.

INTRODUCTION: Febrile neutropenia is a common cause in morbidity and mortality during treatment of hematological neoplasms. METHODS: Subjects included all cases admitted under hematology department with febrile neutropenia from February to June 2018. Each febrile episode was investigated by standard investigations (Blood culture, Chest x ray etc.); Procalcitonin (PCT) and c reactive protein (CRP) was sent at fever onset 0, 24, 48 h, day 7 and day 14. RESULTS: Data was analyzed for 52 febrile episodes in 50 patients. PCT cut off value at 24 h of ≤1.2 ng/ml had a sensitivity and specificity of 62.5% and 87.5% for discriminating Invasive fungal infection (IFI) and Microbiologically documented infection (MDI) (p = 0.033). PCT had a negative predictive value of 70% for the diagnosis of IFI as compared to MDI. CRP cut off >160 mg/dl at 48 h was suggestive of fever due to fungal infection with a sensitivity of 100%, specificity of 48%, PPV of 33.3% and NPV of 100%. CRP at 24 and 48 h of fever was useful to distinguish non-infectious causes of fever from infectious causes. CONCLUSION: PCT at 24 h and CRP at 48 h was useful in identifying fungal infection. CRP was a better marker when compared to PCT for identifying disease fever.

Pediatric myelofibrosis: WHO 2024 update on myeloproliferative neoplasms calling?

OBJECTIVES: Pediatric myelofibrosis is a rare entity with the largest reported series of 19 cases. We describe here the clinicopathological spectrum and outcomes of 15 cases of pediatric myelofibrosis. METHODS: Case files of myelofibrosis of patients less than 18 years were retrieved from January 2016 to January 2019, and patients with idiopathic myelofibrosis after exhaustive work-up were studied. Their clinicopathological profiles were studied and then followed up for resolution and malignant transformation. RESULTS: Of the 15 cases of idiopathic myelofibrosis, transfusion-dependent anemia (14/15) was most common presentation. Only one patient showed leukoerythroblastosis with dacryocytes. Myeloid hyperplasia was seen in 13 of 15 patients and megakaryocytic hyperplasia in 10 patients. Dysmegakaryopoiesis was seen in 8 of 15 patients, and only three had small loose megakaryocytic clustering. None showed hyperchromatic megakaryocytes, intrasinusoidal hematopoiesis, or osteosclerosis. One patient with trisomy 8 tested positive for JAK2V617F. Bone marrow biopsy was hypercellular in 13, and 8 had world health organization (WHO) MF-3 fibrosis. None of the patients developed malignancy, one had spontaneous resolution, and one patient required allogenic stem cell transplant. CONCLUSIONS: Pediatric myelofibrosis is a distinct entity from primary myelofibrosis in adults and merits mention in the WHO manual as a distinct entity.

Outcomes of paroxysmal nocturnal hemoglobinuria in the pediatric age group in a resource-constrained setting.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired clonal stem cell disorder. Eculizumab and bone marrow transplantation are disease-modifying treatments for PNH but may not be readily available in resource-constrained settings. Of 52 pediatric patients with PNH, 20 had classical PNH and 32 had PNH/aplastic anemia (PNH/AA). Median time to diagnosis was 30 months in classical PNH patients. Renal failure was present in four patients (20%). Six (30%) achieved complete response, 10 (50%) achieved partial response with androgens in classical PNH. Two underwent allogenic stem cell transplantation. In the PNH/AA group, 16 (50%) were in CR and seven (21%) were in PR with anti-thymocyte globulin ± cyclosporine.

Concomitant Existence of Paroxysmal Nocturnal Hemoglobinuria in a Patient with Hb E (HBB: c.79G>A) Trait.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal disorder that manifests with bone marrow failure, thrombosis and hemolysis. We present a 28-year-old male who presented with weakness, jaundice and transfusion dependence. On initial investigation, he was found to have anemia with jaundice with hemoglobin (Hb) capillary zone electrophoresis suggestive of Hb E (HBB: c.79G>A) trait. The same anomaly was also found in his mother. However, transfusion requirement was an unusual feature in the patient. As his corrected reticulocyte count was raised along with lactate dehydrogenase (LDH), which was suggestive of a hemolytic process, he was worked-up for the same. However, the direct Coombs test was negative. A bone marrow aspiration and biopsy was done to rule out hypersplenism but it revealed erythroid hyperplasia with reduced iron stores despite normal ferritin and iron studies. This was unusual as the patient had anemia requiring transfusions. He had no history of hemoglobinuria but a PNH by flowcytomety revealed a large clone of 81.2% in granulocytes and 88.5% in monocytes. The patient was started on Danazol and steroids for anemia which improved. He was counseled for matched sibling stem cell transplant. He had a full match with his brother. At the time of this study he awaits his transplant.

Pulmonary Langerhans Cell Histiocytosis: A not so Benign Lesion.

Langerhans cell histiocytosis is a multisystem disease affecting young children. Lung involvement has a myriad of manifestations and the outcomes for these patients have been poorly defined. We present a 2-year-old child who presented with multisystem disease with multiple lung cysts. Treatment consisted of multiagent chemotherapy for 18 months and was associated with a slow but favorable response.

Warm antibody hemolytic anemia-a rare presentation of neonatal lupus.

Neonatal lupus erythematosus (NLE) affects 1%-2% pregnant females with autoimmunity. An infant presented with steroid refractory hemolytic anemia as a manifestation of NLE. A trial of withholding breastfeeding had a transient response, but infant was eventually put on cyclosporin therapy to control the hemolysis. Now he is thriving well and transfusion free.

A tertiary care centre experience with Elranatamab: A report of three cases.

Introduction: The introduction of proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies has changed the treatment paradigm of multiple myeloma. With the advent of these new therapeutic options, life expectancy has substantially increased for myeloma patients which has led to an increased number of patients with triple-class refractory disease. Thus, there remains an unmet need for effective novel therapies with good tolerability and safety profile. Elranatamab, is the most widely used bispecific antibody currently in the Indian setting. However, it has only been used on a clinical trial basis till now, and real-world data especially in the Indian setting is missing. Here, we present our experience with three cases of multi-line treated relapsed/refractory multiple myeloma on elranatamab monotherapy. Case report: We here discuss three of our patients with triple class refractory multiple myeloma who recieved elranatamab monotherapy. While one of our patient had been switched to fortnightly treatment, two patients were still continuing weekly treatment. The common adverse effects observed were grade 1-2 cytokine release syndrome, cytopenias, CMV reactivation and hypo-gammaglobulinemia. While two of our patients are doing well, one patient had grade 3 neurological toxicity, likely drug related and succumbed. Discussion: B-cell maturation antigen is highly expressed on mature B cells and is critical for the survival and proliferation of plasma cells. It has emerged as a novel target for anti-myeloma therapies in the form of bispecific cell engager, antibody-drug conjugates, and chimeric antigen receptor (CAR) T-cell therapies.The phase II MM3 trial showed a promising efficacy with an ORR of 61% with a CR rate of >35%. With a median follow-up of 14.7 months, the median PFS was not reached and the 15-month PFS rate was 50.9%. While it is too early to comment on long term survival with the monotherapy, we here discuss response of Indian patients in the real world setting. Conclusion: Elranatamab monotherapy could prove to be an efficacious option for the treatment of relapsed /refractory multiple myeloma patients with triple-class refractory disease, with limited therapeutic options. However, patients need to be screened for infectious complications with appropriate prophylaxis and immunoglobulin replacement, if required. Also, a high suspicion is required for the neurological complications of the drug and a longitudinal neuro-cognitive screening is required for the patients.

HIV Associated Lymphomas: A Double-Edged Sword.

People with HIV (human immunodeficiency virus) are at higher risk of developing Lymphomas in comparison to people without HIV. The risk of developing lymphomas in patients with HIV continues to persist, even in the HAART era. We retrospectively analysed outcomes of patients with HIV associated lymphomas between Jan 2012 and Oct 2022, with minimum follow up of 6 months. Outcomes have been reported in terms of overall response rate (ORR), overall survival (OS) and event free survival (EFS). Statistical methods such as Kaplan Meier test were used to assess the overall survival and progression free survival, while chi-square test was used to assess factors affecting disease response. Twenty-three patients were identified as HIV associated lymphoma in that duration. Four patients were excluded from the cohort due to insufficient data in the database record. 12 (63.15%) were male and 07 (36.85%) were females with male: female ratio of 1.7:1. Median age was 42 years ranging from 21 to 66 years. 11 (57.9%) patients had stage-4 disease at presentation. Median CD4 counts at diagnosis was 615/µl, ranging from 130 to 1100/µl. DLBCL cases were in majority which showed 60% of CR post 1st line Chemotherapy. At the last follow-up, 04 (21.05%) patients were dead and 15 (78.95%) patients were alive. 10 years Overall survival [OS] and Progression Free Survival [PFS] was found to be 78.95% ± 11 at a median follow up of 42.6 months ranging (1.7-114.3) months. HIV associated lymphomas have an acceptable prognosis, despite majority presenting with stage 4 disease, low median CD4 count at diagnosis, concomitant ART, and treatment with intensive chemotherapy.

Real world outcome of B ALL with t (1; 19) (q23; p13)/TCF3::PBX1 in adolescents and adults treated with intensive regimes.

Significant heterogeneity has been reported in outcome of Acute lymphoblastic leukemia with t(1;19)(q23;p13)/TCF3::PBX1 in adolescents and adults leading to a lack of consensus on precise risk stratification. We evaluated clinical outcome of 17 adult ALL cases (≥15 years) with this genotype treated on intensive regimes.13/17 received COG0232 and 4/17 cases received UK-ALL protocol. All achieved CR (100%) with above treatment. End of induction MRD was evaluated in 14/17 cases of which 11 (78.5%) achieved MRD negativity. Total nine patients relapsed (7 marrows, 2 CNS). Overall survival at 2 years was 53.3%. The 2 year estimated PFS was 42.9%. The 2 years CIR was 54.2%. Adults with this genotype perform poorly despite early favorable response. Incorporation of novel immunotherapies and prompt HSCT should be strongly considered with this genotype. Targeted NGS panels for additional genetic aberrations can further help in risk stratifying and guiding therapy for this genotype.

Immunosuppression Boost With Mycophenolate Mofetil for Mixed Chimerism in Thalassemia Transplants.

Declining mixed chimerism (MC) portending impending graft failure is an undesirable outcome. However, for hemoglobinopathies in a stable state of MC, residual host cells persist without rejection in 30% to 40% of patients after hematopoietic stem cell transplantation (HSCT). Early detection and level of MC have been attributed to be significant in predicting the outcome of MC. Common clinical approach on MC is removal of immunosuppression. We retrospectively evaluated MC in transfusion dependent thalassemia patients who underwent HSCT in our institution between September 2013 and January 2022 to determine the outcome of MC on the basis of our approach of immunosuppression boost in comparison to conventional approach of immunosuppression tapering. Among 90 patients, 22 (24.4 %) had MC at some time point after transplantation with a median follow-up of 496 (67-1492) days. Immunosuppression withdrawal was done in 12 (54.5%) patients, whereas immunosuppression boost was given in 8 (36.3%) patients. In the immunosuppression withdrawal group, 2 (16.6%) patients evolved to complete chimerism, 5(41.6%) patients had persistent MC (PMC), whereas 5 (41.6%) patients had secondary rejection. All these rejections were at median of 186 (89-251) days after transplantation. In the immunosuppression boost group, all patients (n = 8) had PMC with no secondary rejection until median follow-up of 255(97-812) days after transplantation. We acknowledge that we need more experience with our unconventional approach of immunosuppression boost to obtain statistical significance in comparison to the conventional approach of tapering of immunosuppression.

Attenuated Dose Dasatinib in Newly Diagnosed Chronic Myeloid Leukemia Chronic Phase Patients in India.

BACKGROUND: BCR-ABL Tyrosine kinase inhibitors (TKI's) are most successful of targeted therapies and are currently considered the cornerstone in the management of patients with chronic myeloid leukemia (CML). A recent study reported excellent outcomes of Dasatinib 50mg with better sustained response. Therefore, we aim to evaluate the molecular responses and safety of upfront Dasatinib 50mg in Indian CML-Chronic Phase patients. METHODS: It was an observational single-centre study. CML-CP patients started on Dasatinib 50mg daily were offered to participate in this study. Data of imatinib was collected retrospectively as a comparator group. RESULTS: Between June 2020 to Feb 2022, fifty patients were included in the dasatinib 50mg once daily group. Median age was 40 yrs. ranging from (19 to73) years. At a median follow up of 9.2 months, 49 patients completed three months treatment, out of which 48 patients were evaluated as one patient stopped medication after a month due to financial constraints. The response rate at three months for dasatinib 50mg daily and Imatinib were 68.75% and 69.7% respectively. At 12 months, 68% and 66.6% patients achieved major molecular response [MMR] in dasatinib 50mg and imatinib groups respectively. CONCLUSION: In conclusion, low dose dasatinib is safe and effective as an upfront therapy in CML-CP. Early molecular response [EMR] rates were comparable in low dose dasatinib and imatinib arm but deep molecular responses were significantly higher in low dose dasatinib arm. Dasatinib, taken daily at a dose of 50mg, may offer a new, alternative choice as generic versions are available now for frontline therapy in CML-CP.

Effect of antibiotic de-escalation on clinical outcomes in patients with carbapenem-resistant Enterobacteriaceae bacteremia (CRE) in the hematology-oncology setting.

Introduction: Carbapenem-resistant Enterobacteriaceae (CRE) infections are associated with poor outcomes, particularly among hematology-oncology patients. Appropriate use (selection and de-escalation) of antibiotics is a key component of management of febrile neutropenia particularly in high CRE prevalence regions like India. Methods: This was a retrospective study done (April 2019-December 2021) in a dedicated oncology center in North India, which assessed the case records of the patients undergoing therapy for hematological malignancies who were diagnosed with CRE bacteremia. Demographic, clinical and microbiological data, as well as antibiotic prescription patterns were studied. Inter-group analysis was done between an antibiotic stewardship cohort (avoiding CRE therapy empirically or stopping CRE therapy if cultures negative; as per suggestions of the AMS team) and a non-antibiotic stewardship cohort (continuation of empirical CRE therapy; de-escalation advice was not followed). Results: A total of 139 patients were identified, with median age of 41 years (range 13-74) out of which 82 (58.9%) were males. Acute myeloid leukemia (66.2%) was the most common malignancy, followed by lymphoma (8.6%) and myeloma (8.6%). Nearly 30% of patients were post allogenic stem cell transplant. Klebsiella pneumoniae was the predominant organism (78.4%) and combination of NDM+OXA-48 (46.3%) was the most common carbapenemase gene detected followed by OXA-48 alone (34.7%). Overall, 28-day mortality was 26.6%. On binary logistic regression analysis, lack of compliance with antibiotic stewardship intervention was an independent predictor of mortality (p=0.005). Conclusions: Prior exposure to empirical CRE therapy or failure to de-escalate was associated with poor outcomes in patients with CRE bacteremia, which gives us a window of antibiotic stewardship in febrile neutropenia.

FLAG based v/s Standard 3 + 7 induction therapy in treatment naïve Acute Myeloid Leukemia: Time to think "beyond anthracyclines".

Daunorubicin and Cytarabine (DA; 3 + 7) has been the standard frontline Acute Myeloid Leukemia (AML) induction regimen resulting in Complete Remission (CR) rates of 50-70%. It is associated with induction mortality of 15-30%. We report a comparative analysis of DA versus fludarabine, cytarabine, G-CSF (FLAG) + /- Venetoclax in resource constrained settings. We conducted a single center, retrospective analysis of 37 treatment naïve fit AML patients from May 2021 to December 2022 who received either standard DA regimen (Group 1) or FLAG + /- Venetoclax (Group 2). The median patient age was 36.6 years in DA arm (n = 18) as compared to 40.1 years in FLAG arm (n = 19). CR rates at day 28 were 55.5% in group 1 and 89.4% in group 2 (odds ratio [OR], 7.20; 95% confidence interval [CI], 1.274 -40.678; P = 0.012). Patients in FLAG based therapy arm had shorter duration of neutropenia (P = 0.003), fewer episodes of grade 3 febrile neutropenia (P = 0.0228), shorter duration of antibiotic therapy (P = 0.03), lesser need of 3rd line antibiotic therapy (P = 0.0228). Mortality rates were 16.6% (n = 3) in (group 1) and 0% (n = 0) in (group 2) (p = 0.105). Our analysis supports that FLAG based induction regimen is an effective and well-tolerated therapy in treatment naïve fit AML patients.

Candida Empyema in Febrile Neutropenia - Augmented value of direct inoculation into BacT/Alert blood culture vials.

Candida empyema is an uncommon complication of febrile neutropenia. We present 4 such cases which highlight the importance of direct inoculation of body fluids in automated blood culture bottle leading to increased yield. Our cases and review of literature also highlight that echinocandins have poor penetration into pleural fluid; azoles (especially voriconazole) should be preferred as drug of choice.

Pneumocystis jirovecii pneumonia [PJP]: An unrecognized concern in AML patients on Venetoclax.

Pneumocystis jirovecii pneumonia (PJP) is infrequently found in patients with acute myeloid leukemia (AML) whereas its more commonly found in lymphoid malignancies like acute lymphoblastic leukemia and various lymphomas. AML patients are conventionally treated with intensive chemotherapeutic regimen which includes Daunorubicin, Idarubicin, Cytarabine and various other drugs. Trimethoprim/Sulfamethoxazole prophylaxis is not routinely administered to such patients. In recent years, targeted therapies like Venetoclax which is a Bcl-2 inhibitor have been introduced for AML treatment which is given in combination with other chemotherapy and targeted molecules. There is tremendous use of Venetoclax for AML recently specially in unfit and elderly population. We are witnessing this uncommon infection more commonly in those patients treated with Venetoclax based therapy. We report the case series of five patients of AML who were treated with Venetoclax based therapy and had subsequently developed PJP leading to death in four of them. The incidence of PJP was 13.2% among the patients treated with Venetoclax based treatment at our institution in that timeframe. The low index of suspicion led to delay in diagnosis and thereby treatment. Such an association of Venetoclax and Pneumocystis jirovecii pneumonia has not been reported till date, so this prompts for early detection and treatment of this potentially life threatening but treatable infection. So the role of routine prophylaxis with Trimethoprim/Sulfamethoxazole in those receiving Venetoclax based therapy in AML patients merits a thought.