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.

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.

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.

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.

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.

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.

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.

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.

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.

Proportion of CD34+CD38-CD123+ Leukemia Stem Cells at Diagnosis Varies in ELN Risk Groups and an Emerging Novel Marker for Prognosticating the Intermediate Risk patients of Acute Myeloid Leukemia: A Prospective Study.

The proportion of CD34 + CD38 - CD123 + leukemia stem cells (LSCs) at diagnosis of Acute Myeloid Leukemia (AML) correlated with induction remission (IR), relapse free survival and overall survival in few studies. Prospectively bone marrows of AML patients were immunophenotyped for CD34 + CD38 - CD123 + LSCs at baseline using sequential gating, relevant clinical and laboratory data collected and clinical outcomes were studied.The patients (n = 47) were risk stratified as favorable risk, intermediate risk and adverse risk. The percent of LSCs at baseline in favorable risk group (mean = 13.06%) was significantly less than the adverse (mean = 34.8%, p = 0.027) and the intermediate risk group (mean = 53.2%, p = 0.001). On further analysis, 12 patients attaining IR in intermediate risk group had significantly less LSCs than 15 in non-IR group (mean = 21.18%; range 3-85.6% vs mean = 73.85%; range 12.1-97.9%, p = 0.0002). Of all 47 patients, the proportion of LSCs at baseline was significantly less in those achieving IR (p = 0.024) and correlated with time to response (TTR) (rs = 0.432). Thus to conclude, the proportion of CD34 + CD38 - CD123 + LSCs at diagnosis is less in the favorable than the intermediate and adverse risk groups and is  an emerging novel marker for predicting remission in the prognostically diverse intermediate risk group.

Clinico-Hematological Profile of Paroxysmal Nocturnal Hemoglobinuria in Indian Patients: FLAER Flow Cytometry Based Experience from an Indian Tertiary Care Centre.

PNH is a rare disease with wide spectrum of intra-vascular hemolysis and thrombosis to sub-clinical PNH clones. We aimed to study the clinico-hematological profile and clone size on granulocytes and monocytes of PNH patients classified as per International PNH Interest Group recommendations. A retrospective analysis of clinico-hematological profile of 112 PNH clone positive patients by FLAER based flow cytometry between January and September 2017 done and classified into classical PNH, PNH with aplastic anemia or myelodysplastic syndrome (PNH-AA/MDS) and sub-clinical PNH clones (PNH-sc). Of 112 patients, majority were PNH-sc (62) followed by PNH-AA/MDS (34) and classical PNH (16). The commonest clinical feature was anemia in all 3 groups followed by jaundice (87.5%) in classical PNH and fever in PNH-AA/MDS (64.7%) and PNH-sc (48.4%). Thrombosis was present in 25% (4/16) classical PNH and 2.9% (1/34) of PNH-AA/MDS. The mean hemoglobin, reticulocyte count and LDH was higher in classical PNH. Bone marrow was predominantly hypercellular in classical PNH (11/16) and hypocellular in PNH-AA/MDS (31/34) and PNH-sc (50/62) with dyserythropoiesis predominantly in PNH-AA/MDS (83.8%) and PNH-sc (74.1%). Marrow iron was reduced in 62.2% classical PNH contrary to increased in PNH-BMF (58%) and PNH-sc (91%). The mean clone size in PNH-sc was significantly lower with > 50% in 16.2% patients. Three patients with MDS-MLD and MDS-MLD-RS in PNH-sc had > 80% clone on granulocytes and monocytes. Most PNH patients in Indian setting are PNH-sc with significantly lower clone, however, a clone size > 50% is not uncommon in Indian PNH-sc.