Impact of intended and relative dose intensity of R-CHOP in a large, consecutive cohort of elderly diffuse large B-cell lymphoma patients treated with curative intent: no difference in cumulative incidence of relapse comparing patients by age.

BACKGROUND: The increasing incidence of diffuse large B-cell lymphoma (DLBCL) in ageing populations places a significant burden on healthcare systems. Co-morbidity, frailty, and reduced organ and physiological reserve contribute to treatment-related complications. The optimal dose intensity of R-CHOP to optimize outcome across different ages with variable frailty and comorbidity burden is unclear. OBJECTIVES AND METHODS: We examined the influence of intended (IDI) and relative (RDI) dose intensity of the combination of cyclophosphamide and doxorubicin, age and comorbidity on outcomes for DLBCL patients ≥70 years in a representative, consecutive cohort across eight UK centres (2009-2018). We determined predictors of survival using multivariable Cox regression, and predictors of recurrence before death using competing risks regression. RESULTS: Porgression-free survival (PFS) and overall survival (OS) were significantly inferior in patients ≥80 vs. 70-79 years (P < 0.001). In contrast, 2-year cumulative relapse incidence, when accounting for non-relapse mortality as a competing risk, was no different between 70-79 vs. ≥80 years (P = 0.27) or comorbidity status (CIRS-G: 0-6 vs. >6) (P = 0.27). In 70-79 years, patients with an IDI ≥80% had a significantly improved PFS and OS (P < 0.001) compared to IDI < 80%. Conversely, in patients ≥80 years, there was no difference in PFS (P = 0.88) or OS (P = 0.75) according to IDI <80% vs. ≥80%. On multivariable analysis, when comparing by age, there was a significantly higher cumulative relapse rate for patients aged 70-79 years with an IDI <80% (vs. >80%) (P = 0.04) but not for patients ≥80 years comparing IDI (P = 0.32). CONCLUSION: 'R-mini-CHOP' provides adequate lymphoma-specific disease control and represents a reasonable treatment option in elderly patients ≥80 years aiming for cure.

An international evaluation of CODOX-M and CODOX-M alternating with IVAC in adult Burkitt's lymphoma: results of United Kingdom Lymphoma Group LY06 study.

BACKGROUND: Burkitt's lymphoma (BL) is a rare and rapidly progressive form of B-cell non-Hodgkin's lymphoma. Cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate (CODOX-M)/ifosfamide, etoposide and high-dose cytarabine (IVAC) is a highly effective alternating non-cross-resistant regimen developed by Magrath et al. (Magrath I., Adde M., Shad A. et al. J Clin Oncol 1996; 14: 925-934) at the US National Cancer Institute. The aim was to confirm these results in a larger, international, multi-centre study using International Prognostic Index-based criteria to assign prognostic groups, whilst slightly simplifying the protocol. PATIENTS AND METHODS: A phase II study where: (i) low risk (LR) patients were treated with three cycles of modified CODOX-M; and (ii) high risk (HR) patients received treatment with four cycles of alternating modified CODOX-M and IVAC chemotherapy. Target of 60 patients, fit for protocol treatment, from 16 to 60 years of age with locally diagnosed, non-HIV-related, non-organ-transplant-related BL. RESULTS: Results are given for 52 of 72 registered patients whose pathological eligibility was confirmed by central pathology review: 12 LR plus 40 HR. The majority of patients (n = 41) completed protocol treatment, but toxicity was severe, especially myelosuppression and mucositis. Overall, 2-year event-free survival (EFS) was 64.6% (95% CI 50.4% to 78.9%) and 2-year overall survival (OS) was 72.8% (95% CI 59.4% to 86.3%). For LR, 2-year EFS was 83.3% and OS was 81.5%. For HR, 2-year EFS was 59.5% and OS was 69.9%. CONCLUSIONS: This study confirms high cure rates with this CODOX-M/IVAC approach.

Genetic heterogeneity in heterocellular hereditary persistence of fetal hemoglobin.

A large English pedigree in which heterocellular hereditary persistence of fetal hemoglobin (HPFH) segregates is described. beta-globin cluster deletions and gamma gene promoter mutations associated with HPFH have been excluded. Of particular importance in this pedigree is the absence of any cosegregating hemoglobinopathy, thus allowing observation of the segregation pattern of this form of HPFH without the complicating effect of a beta-globin gene mutation. Information gained in this study confirms that the extent of elevation of hemoglobin (Hb) F and F cells varies between affected individuals. There are one example of incomplete penetrance and three examples of father-to-son transmission, thus excluding X-linked inheritance. Consistent with previous reports, the most likely mode of inheritance is autosomal codominant. Linkage studies using a beta-globin cluster microsatellite show no evidence of linkage to this chromosomal region implicating the presence of trans-acting regulatory factor(s). We have recently mapped one such locus to the chromosome 6q region in a very large Asian-Indian pedigree. Linkage to chromosome 6q in the English pedigree was excluded, thus indicating the presence of genetic heterogeneity in heterocellular HPFH.

Systemic mastocytosis--a case treated with interferon alpha and radiotherapy.

Systemic mastocytosis is uncommon. Symptoms result from local infiltration and degranulation of mast cells. Reports in the literature describe successful use of interferon alpha and radiotherapy to produce reduction in symptoms and bulk of disease. We report a patient who responded to radiotherapy but not interferon alpha.

Genetic diagnosis of Gaucher's disease.

The inherited disorder Gaucher's disease can be caused by various mutations in the glucocerebrosidase gene. Some mutations may be associated with greater severity, and there is a need for methods of gene analysis that would facilitate screening and diagnosis. We have studied the molecular basis of Gaucher's disease in twelve unrelated patients of diverse ethnic origin by means of the amplification refractory mutation system (ARMS). Primers for the polymerase chain reaction were designed to discriminate between mutant and wild-type alleles of glucocerebrosidase and to allow separation from products of the related pseudogene. The nucleotide 1226 mutation (asparagine 370----serine) and 84GG (an insertional frameshift mutation) were found exclusively in five patients of Ashkenazi Jewish descent (7 and 2 of the 10 disease alleles, respectively). Two point mutations, at nucleotides 1448 (leucine 444----proline) and 1504 (arginine 463----cysteine), were found in 4 and 3 alleles, respectively; they were associated with rapidly progressive disease and neurological involvement in non-Jewish patients. The ARMS procedure for direct detection of common mutations in glucocerebrosidase will facilitate genetic counselling and screening programmes for individuals at risk of Gaucher's disease.

Alpha-thalassemia caused by a large (62 kb) deletion upstream of the human alpha globin gene cluster.

We describe a family in which alpha-thalassemia occurs in association with a deletion of 62 kilobases from a region upstream of the alpha globin genes. DNA sequence analysis has shown that the transcription units of both alpha genes downstream of this deletion are normal. Nevertheless, they fail to direct alpha globin synthesis in an interspecific hybrid containing the abnormal (alpha alpha)RA chromosome. It seems probable that previously unidentified positive regulatory sequences analogous to those detected in a corresponding position of the human beta globin cluster are removed by this deletion.

Variation of erythroid and myeloid precursors in the marrow and peripheral blood of volunteer subjects infected with human parvovirus (B19).

Infection of normal individuals with human parvovirus (B19) results in a mild disease (erythema infectiosum) but gives rise to aplastic crises in patients with chronic hemolytic anemias. The effects of this disease on hemopoiesis were investigated following intranasal inoculation of the virus into three volunteers. A typical disease ensued with a viremia peaking at 9 d. Marrow morphology 6 d after inoculation appeared normal but at 10 d there was a severe loss of erythroid precursors followed by a 1-2-g drop in hemoglobin, and an increase in serum immunoreactive erythropoietin. Erythroid burst-forming units (BFU-E) from the peripheral blood were considerably reduced, starting at the time of viremia and persisting for 4-8 d depending on the individual. Granulocyte-macrophage colony-forming units (CFU-GM) were also affected but the loss started 2 d later. Both CFU-GM and BFU-E showed a sharp overshoot at recovery. In the marrow, BFU-E and CFU-E were reduced at 6 and 10 d in the individual having the longest period of peripheral progenitor loss. In contrast, there was an increase in BFU-E and CFU-E in the subject with least change in peripheral progenitors. In the third subject, with an intermediate picture, there was a loss at 6 d but an increase at 10 d of erythroid progenitors. It is suggested that the architecture of the marrow might partially isolate progenitors from high titers of virus in the serum and individual variation in this respect might give the results observed.

Frequency of severe neutropenia associated with amodiaquine prophylaxis against malaria.

6 out of 7 patients with severe neutropenia associated with the use of amodiaquine for malaria prophylaxis amodiaquine (400 mg weekly) plus proguanil (200 mg daily); 1 of these patients had also taken cotrimoxazole and another had taken sulphaguanidine. The 7th patient had taken amodiaquine alone, but at a higher dose. A retrospective analysis suggests that the frequency of severe neutropenia complicating amodiaquine taken prophylactically may be as high as 1 in 2000.

Detection of metastatic tumour cells in routine bone marrow smears by immuno-alkaline phosphatase labelling with monoclonal antibodies.

The present study describes 11 cases (10 carcinomas, one rhabdomyosarcoma) in which immuno-alkaline phosphatase labelling with monoclonal antibodies was used to demonstrate metastatic cells in routine smears of aspirated bone marrow. Carcinoma cells were detected using antibodies against epithelial cytokeratins, milk fat globule membrane antigen and carcinoembryonic antigen, and rhabdomyosarcoma cells with monoclonal anti-desmin. In four of the carcinoma cases it had not been possible to identify malignant cells in routinely stained marrow smears, whilst the case of disseminated rhabdomyosarcoma had initially been diagnosed (and treated) as a case of acute lymphoblastic leukaemia. The anti-cytokeratin antibody was found to be the most valuable of the anti-epithelial reagents used, since it labelled malignant cells in all of the 10 cases of carcinoma and gave the strongest reactions. These results suggest that immunocytochemical labelling should be used in cases of suspected carcinoma whenever conventional examination of marrow smears yields negative results, and furthermore (as illustrated by the case of rhabdomyosarcoma) that the technique is of value for identifying the true nature of poorly differentiated neoplasms in bone marrow.

Hepatic sequestration in sickle cell anaemia.

Several episodes of acute hepatic enlargement associated with a dramatic fall in haemoglobin concentration were observed in two patients with sickle cell anaemia. No appreciable disturbances of liver function or signs of cardiac failure were evident. The most likely mechanism was sequestration of sickled erythrocytes in the liver. This complication, which may have a basis similar to that of splenic sequestration and the sickle lung syndrome, may be easily overlooked unless the size of the liver is regularly monitored in patients with sickle cell crisis.