Mohamed A. Samra

Clinical prognostic factors of diffuse large B cell non-Hodgkin lymphoma: A retrospective study

BACKGROUND Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of NHL in Egypt. It represents about 49% of NHL presenting to the National Cancer Institute (NCI), Cairo University. CHOP regimen is the standard treatment used for NHL since the 1970s with only 30-40% overall survival. Recently, integration of Rituximab became a standard of care for patients with DLBCL. However, its widespread use in developing countries is still limited by the lack of financial coverage. Clinical prognostic factors, as well as the pathological markers, are mandatory to individualize treatment. AIM The aim of the study was to evaluate the clinical risk stratification models including the age adjusted International prognostic index (aaIPI), patients profile and dose intensity (DI) of Cyclophosphamide and Doxorubicin as effective tools for predicting the outcome and prognosis of our DLBCL patients treated with first line CHOP regimen. PATIENTS AND METHODS This retrospective study included 224 patients with diffuse large B cell lymphoma who were treated with 3-8 cycles of CHOP regimen at the Medical Oncology Department, NCI, Cairo University during the time period from 1999 to 2006. RESULTS One hundred and seventy-eight patients (79.5%) achieved CR after the CHOP regimen with an observation period of 51 months. The median survival time was 12 months. The OS and DFS at 2 years were 82% and 68.8%, respectively. The univariate analysis of predictive factors for response to treatment showed that the CR rate was significantly affected by aa-IPI and its elements (performance status, stage & LDH), extranodal lesions and DI of Cyclophosphamide and Doxorubicin. The CR rate was 96.9%, 91.2%, 73.9% and 55.6% in cases with aa-IPI 0, 1, 2 and 3, respectively (p<0.001) and it was 82.4%, 81.9% versus 50% in cases with no extranodal site, one extranodal site and two extranodal sites, respectively (p=0.01). As regard DI of Cyclophosphamide, with DI below or equal to the median (249 mg/m(2)/week) the CR rate was 69%, while with DI above the median the CR rate was 87.7% (p=0.001). For Doxorubicin, the CR rate was 72.3% with DI below or equal to the median (16.5 mg/m(2)/week), however, it was 86.6% with DI above the median (p=0.008). The OS rate was significantly affected by aa-IPI as it was 89.8% in cases of aa-IPI 0+1 versus 75.8% in those of aa-IPI 2+3 (p=0.03). DI of Cyclophosphamide and Doxorubicin significantly influenced the OS. The OS rate was 74% with DI of Doxorubicin below or equal to the median versus 96% in cases with DI above the median (p=0.02). For Cyclophosphamide the OS rate was 72.7% with DI below or equal to the median versus 96.3% in cases with DI above the median (p=0.01). The tumor bulk (with a median tumor size of 5 cm) affected the OS, which was 91.23% versus 86.8% in the tumor bulk less than and more than or equal to the median, respectively (p=0.05). By multivariate analysis of predictive factors for response to treatment, the CR rate was significantly affected by the number of extranodal sites and the clinical staging of diffuse large B cell lymphoma. However, OS rate was strongly associated with the bulk of the tumor and the clinical staging of diffuse large B cell lymphoma. CONCLUSION DI of Cyclophosphamide and Doxorubicin is important in the future treatment regimen plan for DLBCL especially in high risk cases. In addition to aa-IPI and its elements, extra nodal sites and bulk of the tumor proved to be significant predictors and prognostic factors for DLBCL treatment outcome.

Allogeneic hematopoietic stem cell transplantation for non-malignant hematological disorders

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) from a geno-identical matched sibling (MSD) is one of the most successful therapies in patients with non-malignant hematological disorders. This study included 273 patients with severe aplastic anemia (SAA), 152 patients with B-Thalassemia major (BTM), 31 patients with Fanconi’s anemia (FA), 20 patients with congenital immunodeficiency diseases (ID), and 13 patients with inherited metabolic disorders (IMD) allografted from a MSD. In SAA, the 8-year overall survival (OS) of the whole group patients was 74%. OS was significantly better in patients conditioned with fludarabine and cyclophosphamide (Flu/Cy) than in those who received cyclophosphamide and antithymocyte globulin (Cy/ATG) (p = 0.021). Acute graft-versus-host disease (aGVHD) grade II–IV occurred in 15% while chronic GVHD (cGVHD) occurred in 28%. In BTM, the 12-year disease-free survival (DFS) of the whole group of BTM patients was 72.4%. DFS was 74% for peripheral blood stem cell (PBSC) group compared to 64% in the BM stem cell group. The incidence of graft rejection was significantly lower in patients who received PBSC than in those who received BM (9% vs 25%) (p = 0.036). AGVHD grade II–IV and cGVHD occurred in 15% and 12% of the whole group of BTM patients respectively. In FA, the 5-year OS was 64.5%. Graft rejection occurred in 10% of patients. Grade II–IV aGVHD occurred in 16% while cGVHD occurred in 4%. In ID, the 5-year OS was 62%. Graft rejection occurred in two (10%) patients. Three patients (15%) developed grade II–IV aGVHD, 2 of them progressed to secondary cGVHD. In IMD, OS was 46% at 5 years. Graft rejection occurred in 8% of patients. AGVHD grade II–IV occurred in 15% while cGVHD occurred in 14%. In conclusion, Allo-HSCT provides a higher DFS rate over conventional therapies for patients with non-malignant hematological disorders with prolonged survival.

CTLA-4 polymorphism and clinical outcome post allogeneic hematopoietic stem cell transplantation.

CTLA-4 inhibitory molecule plays an important role in regulating T cell activation. It is considered a crucial element in keeping the immune balance and has been implicated in cancer, autoimmunity and transplantation immunology. Inconsistent observations are reported regarding its association with hematopoietic stem cell transplantation (HSCT). Genotyping of CTLA-4 was performed in recipients and their HLA-matched donors for +49A/G and CT60 polymorphisms (80 and 94 pairs, respectively) using PCR-RFLP. No association was encountered between both polymorphisms in patients and donors and acute or chronic graft versus host disease. Significant association was observed between recipient +49A/G G allele and lower disease-free survival and overall survival compared to AA genotype (HR: 2.17, p = 0.03, 95% CI: 1.05-4.48 and HR: 2.54, p = 0.01, 95% CI: 1.16-5.54), respectively. Our results suggest that CTLA-4 genotyping may predict outcome in patients post HSCT. To validate our results, further studies on a larger cohort are needed.

Primary gastrointestinal lymphoma in an Egyptian district: a study using a population-based cancer registry.

INTRODUCTION Gastrointestinal lymphoma (GIL) is the most common extranodal form of non-Hodgkins lymphoma (NHL) with geographical and age variation of its various subtypes. AIM To study GIL in Gharbiah, Egypt and to recognize the treatments employed and their outcomes including survival. METHODS This is a retrospective study. Between 2000 and 2002, 40 adult patients with GIL were identified in the Gharbiah population based cancer registry (GPBCR); 26 cases of whom were treated at Tanta Cancer Center (TCC). RESULTS GIL in Gharbiah, Egypt represented 6.2% of all GIT cancers. The median age was 47 years with slight male predominance. The commonest primary site was the stomach followed by the colon/rectum then the small intestine (67.5%, 25% and 7.5%, respectively). The commonest histological subtypes were the diffuse large B-cell (41.5%) followed by marginal zone B-cell (39%). The commonest symptoms were abdominal pains followed by vomiting. Only 18% of GILs were surgically resected. Most patients (77%) received chemotherapy with a 60% complete response (CR) rate. Once in CR, relapses are occasional. The median overall survival (OS) and progression free survival (PFS) were 31 and 14 months (95% CI, 13.2-48.7 and 6.4-21.6 months, respectively). Gastric primary site and diffuse large B cell subtype carry a non-significant worse OS and PFS than those of other sites and subtypes. CONCLUSIONS GILs in Gharbiah, Egypt are characterized by predominance of male gender, gastric site and marginal zone histology. Survival is worse for gastric and diffuse large B-cell GILs compared to other sites and histologies.

The prognostic significance of minimal residual disease in adult Egyptian patients with precursor acute lymphoblastic leukemia

BACKGROUND Minimal residual disease (MRD) studies in adult acute lymphoblastic leukemia (ALL) give highly significant prognostic information superior to other standard criteria as age, gender and total leucocytic count (TLC) in distinguishing patients at high and low risk of relapse. OBJECTIVES We aimed to determine the value of MRD monitoring by flowcytometry (FCM) in predicting outcome in adult Precursor ALL patients. PATIENTS AND METHODS Bone marrow (BM) samples were analyzed by 4-color FCM collected at diagnosis and after induction therapy (MRD1) to correlate MRD positivity with disease free survival (DFS) and overall survival (OS). RESULTS Study included 57 adult ALL patients (44 males and 13 females) with a median age of 22 years (18-49). DFS showed no significant difference with age, gender and initial TLC (p=0.838, 0.888 and 0.743, respectively). Cumulative DFS at 2 years was 34% for B-lineage ALL (n: 35) and 57% for T-lineage ALL (n: 18) (p = 0.057). Cumulative DFS at 2 years was 7% for MRD1 positive (high risk, HR) versus 57% for MRD1 negative patients (Low risk, LR) (p < 0.001). Cumulative DFS at 2 years was 29% for HR patients (n: 26) versus 55% for LR (n: 27) according to GMALL classification (p = 0.064). Cumulative OS did not differ according to age, gender and TLC (p = 0.526, 0.594 and 0.513, respectively). Cumulative OS at 2 years was 36% for B ALL (n: 39) versus 77% for TALL (n: 18) (p = 0.016) and was 49% for Philadelphia chromosome (Ph) negative patients versus 0% for Ph-positive patients (p < 0.001). Regarding MRD1, OS at 2 years was 18% for MRD1 HR (n: 17) versus 65% for MRD1 LR (n: 38) (p < 0.001). OS was 35% for high-risk patients (n: 30) and 62% for low-risk patients (n: 27) classified according to GMALL risk stratification (p = 0.017). CONCLUSION MRD by FCM is a strong independent predictor of outcome in terms of DFS and OS and is a powerful informative parameter in guiding individual treatment in ALL patients.

Comparable Outcome of Allogeneic versus Autologous Hematopoietic Peripheral Blood Stem Cell Transplantation in Acute Myeloid Leukemia Patients with Normal Karyotype and FLT3-ITD Negative

Introduction: Optimal post-remission treatment for acute myeloid leukemia patients with normal karyotype (AMLNK) in first complete remission (CR1) who lacks an HLA identical donor is still not well-defined. Aim of the Work: To compare the outcome of allogeneic versus autologous peripheral blood stem cell transplantation (PBSCT) in adult AML patients regarding toxicities of transplant procedure, transplant-related mortality (TRM), disease free survival (DFS) and overall survival (OS). Patients and Methods: 43 AML patients were included; 34 patients (with a median age 28 years) received myeloablative allogeneic PBSCT from a matched sibling donor while 9 patients (with a median age 36 years) received PBSC autograft. All patients had a normal karyotype (NK), FMS-like tyrosine kinase 3 internal tandem duplication (FLT3 ITD) negative and were in CR1. Results: After a median follow up of 21.5 months (0.3- 46.5), the cumulative 2-year OS and DFS in the allogeneic group were 73.5% and 70.6% respectively, compared to 74.1% and 64.8%, respectively in the autologous group (p=0.690 and 0.768). Increasing number of consolidation cycles (>3) and lower CD34 stem cell dose were associated with lower relapse rates and higher DFS in the autologous group. Conclusion: Preliminary data show a comparable outcome of autologous compared to allogeneic PBSCT in patients with AML-NK and FLT3 ITD negative in CR1. In absence of matched sibling donor, autologous PBSCT may provide an acceptable post remission therapy for patients with low risk molecular profile.

Hematologic malignancies during pregnancy: A review

Graphical abstract

MPN10 score and survival of molecularly annotated myeloproliferative neoplasm patients

Abstract JAK2, CALR, MPL and triple-negative mutational status has a direct impact on symptom severity and disease burden assessed by MPN10 score in myeloproliferative neoplasms (MPNs). Among 93 patients; median MPN10 score was 48 (5–76) in JAK2 mutants versus 25 (4–80) in JAK2 negative (p < .001); 22.5 (4–65) in CALR mutants versus 35 (5–80) in CALR negative (p < .050) and 21 (10–48) in triple negative versus 40 (4–80) in JAK2/CALR/MPL mutants (p < .001). At three years, progression free and overall survival of JAK2-positive versus JAK2-negative patients were 62% versus 100% (p < .001); 85% versus 100% (p = .011) and were 100% versus 78% (p = .067); 100% versus 92% (p = .197) in CALR-positive versus CALR-negative patients and 100% versus 75% (p = .004); 100% versus 90% (p = .015) in triple negative versus mutant patients, respectively. MPN10 score in association with driver gene mutations can be used as a predictor of survival in MPN patients.