The Treatment of Burkitt Lymphoma With the Berlin-Frankfurt-Münster Protocol With Rituximab and Consolidative Autologous Transplantation.

INTRODUCTION: Intensive treatment approaches are required for adult patients with Burkitt lymphoma (BL), although an univocal standard of care still does not exist. The use of frontline autologous stem cells transplantation (ASCT) is debated. PATIENTS AND METHODS: Between 2004 and 2020, 50 patients with BL were treated with the Berlin-Frankfurt-Münster (BFM). Treatment plan consisted of 3 blocks, A (ifosfamide, vincristine, methotrexate, etoposide, and cytarabine), B (vincristine, cyclophosphamide, methotrexate, and doxorubicin), and C (vindesine, methotrexate, etoposide, and cytarabine), each repeated twice, every 28 days. Rituximab was given at day 1 each block. Intrathecal prophylaxis was given once per each block. ASCT was scheduled at the end of the 6 blocks after conditioning. RESULTS: Median age at onset was 38 years (range 16-72); stages III-IV disease was observed in 82% of cases; bulky disease occurred in 44% of the patients, with B-symptoms in 38%. Stem cell harvest was performed in 72% of patients, who all received a subsequent ASCT. The full 6 blocks treatment was completed in 70% of the patients. The overall response rate was 74%, with a complete response rate of 60%. Ten-year overall survival and progression-free survival were 83.7% and 76.0%, respectively, without reaching the median. Ten-year disease-free survival was 80.3%. Grades 3-4 neutropenia, thrombocytopenia, anemia, and mucositis were seen in 96%, 60%, 32%, and 24% of patients. Infections occurred in 60% of patients. CONCLUSION: Intensive treatment according to BFM protocol, with rituximab and ASCT, appears feasible, safe, and highly effective in adult patients with BL, as confirmed by long-term survival rates reflecting response maintenance.

Diffuse large B cell lymphoma characteristics and outcomes during the COVID-19 pandemic in two tertiary centers - an Israeli/ Italian study.

The COVID-19 pandemic posed a major challenge in cancer care worldwide which might have an impact on the management of diffuse large B-cell lymphoma (DLBCL). We conducted a retrospective study comparing characteristics, management, and outcomes of DLBCL patients diagnosed during the first year of the COVID-19 pandemic (1/3/2020-28/2/2021) to those diagnosed in the previous year (1/3/2019-28/2/2020) in two tertiary centers in Italy and Israel. 182 patients were diagnosed with DLBCL during the study period. More patients were diagnosed during the pandemic compared to the year before: 60 vs. 29 and 54 vs. 39 in Italy and in Israel, respectively. Trends towards older age and higher transformation rates were shown during the pandemic. The interval between the initiation of symptoms and diagnosis was longer during the pandemic. Five and four patients were diagnosed with COVID-19 during treatment in Italy and in Israel, respectively. there was no difference in dose density and intensity of treatment, before and during the pandemic. The median follow-up during and before the pandemic was 15.2 and 25.5 months, respectively. Progression-free survival (PFS) was slightly shorter during the pandemic compared to the year before (64.9% vs. 70.6%; p = 0.0499). In multivariate analysis, older age and transformed disease were independently related to PFS, while diagnosis of DLBCL during the pandemic was not. Despite the challenges caused by COVID-19 pandemic, the management of DLBCL patients remained unchanged including dose density and intensity. Nevertheless, a shorter PFS during the outbreak might be attributed to differences in patients' characteristics.

Economic evaluation of anti-CD19 CAR T-cell pathway for large B-cell lymphomas in the real-life setting: the experience of an Italian hub center in the first three years of activity.

Poor literature report actual and detailed costs of chimeric antigen receptor (CAR) T-cell pathway in a real-life setting. We retrospectively collect data for all patients with relapsed/refractory aggressive large B-cell lymphoma who underwent leukapheresis between August 2019 and August 2022. All costs and medical resource consumption accountability were calculated on an intention-to-treat (ITT) basis, starting from leukapheresis to the time when the patient (infused or not) exited the CAR T-cell pathway for any reason. Eighty patients were addressed to leukapheresis and 59 were finally infused. After excluding CAR-T product cost, the main driver of higher costs were hospitalizations followed by the examinations/procedures and other drugs, respectively 43.9%, 26.3% and 25.4% of the total. Regarding costs of drugs and medications other than CAR T products, the most expensive items are those referred to AEs, both infective and extra-infective within 30 days from infusion, that account for 63% of the total. Density plot of cost analyses did not show any statistically significant difference with respect to the years of leukapheresis or infusion. To achieve finally 59/80 infused patients the per capita patients without CAR-T products results 74,000 euros. This analysis covers a growing concern on health systems, the burden of expenses related to CAR T-cell therapy, which appears to provide significant clinical benefit despite its high cost, thus making economic evaluations highly relevant. The relevance of this study should be also viewed in light of continuously evolving indications for this therapy.

Prolonged Complete Response with Lenalidomide in a Relapsed Diffuse Large B-Cell Lymphoma, Leg-Type: A Case Report.

INTRODUCTION: For primary cutaneous diffuse large B-cell lymphoma, leg-type (PCDLBCL-LT), there are no uniform recommendations for second-line treatment in case of relapse. CASE PRESENTATION: Here, we present the case of an elderly relapsed/refractory PCDLBCL-LT patient who obtained a prolonged clinical complete remission with lenalidomide. CONCLUSION: Lenalidomide as single agent led to an unexpected long complete response with manageable toxicity.

Endobronchial Presentation of Hodgkin Lymphoma Responding to Pembrolizumab: A Case Report.

An endobronchial localization of Hodgkin lymphoma is rare, and few experiences since the 1900s have been reported in the literature. Here we report the first case of a relapsed/refractory Hodgkin lymphoma with a critical vegetative mass at the level of the trachea successfully treated with pembrolizumab.

Droplet digital polymerase chain reaction for the assessment of disease burden in hairy cell leukemia.

BRAFV600E mutation is the pathogenic driver of hairy cell leukemia (HCL) found in the vast majority of cases both at onset and during recurrences. The identification of the mutated allele in blood and marrow correlates with the presence of neoplastic cells and can be considered a marker of active disease. Likewise, the absence of the mutation after treatment may indicate a state of deep response. The BRAFV600E burden was measured by droplet digital polymerase chain reaction (ddPCR) and expressed as fractional abundance in 35 HCL patients at different stages of disease (onset, relapse, complete response [CR] after treatment, long-term remission) in peripheral blood and/or bone marrow (when available). Mean values of fractional abundance for patients at diagnosis, relapse and response, respectively, were 12.26%, 16.52% and 0.02% in peripheral blood and 23.51%, 13.96% and 0.26% in bone marrow. Four patients out of 6 evaluated at response were molecularly negative for BRAFV600E in peripheral blood. Mean fractional abundance in peripheral blood tested in 14 patients with long lasting CR was 0.05%, and 10 patients were BRAFV600E negative. These preliminary results suggest that ddPCR permits to assess the active tumor burden in HCL at different disease phases and support the hypothesis that some patients in CR qualify for a molecular CR.

Clinical Response in Heavily Pretreated Mycosis Fungoides with Pembrolizumab: A Case Report.

Mycosis fungoides (MF) is a disease almost impossible to cure. In the context of heavily pretreated patients, the anti-programmed cell death protein 1 (anti-PD-1) pembrolizumab is a valid therapeutic option. The alteration of the PD-1-PD ligand 1 (PD-L1) axis is often present in MF, and this aspect explains the feasibility of this therapy. We report the case of a 60-year-old woman diagnosed with MF in 2003, Olsen stage IA (T1M0NXBO). Since the moment of the diagnosis, she received 10 lines of therapy, with a short duration of response after each one of them. In April 2020, our patient started pembrolizumab 2 mg/kg every 3 weeks, and she achieved a partial response after the 4th cycle, consistent with the modified severity assessment tool (mSWAT) 1, which she is still maintaining after 10 cycles. No grade ≥3 adverse events were recorded. We conclude that pembrolizumab can induce extremely rapid responses in MF, with very low toxicity.

Hepatosplenic T-Cell Non-Hodgkin Lymphoma Cured with Tandem Autologous and Allogeneic Stem Cell Transplantation.

Hepatosplenic T-cell lymphoma is a very difficult lymphoma to deal with, almost impossible to cure. "Tandem" consolidation therapy with auto-stem cell transplant and allo-stem cell transplant can induce a long-lasting response and potentially cure this disease.

Treatment and outcomes of primary mediastinal B cell lymphoma: a three-decade monocentric experience with 151 patients.

Primary mediastinal B cell lymphoma is a rare entity and often should be promptly treated as a hematological emergency: The initial treatment decision is crucial for the management of this disease. An observational retrospective study was conducted with the aim to improve information on treatment and outcomes of primary mediastinal B cell lymphoma in real practice. After 12 cycles of MACOP-B regimen (methotrexate, doxorubicin, cyclophosphamide, vincristine, bleomycin , and prednisone) with or without rituximab, 120 patients out of 151 (79.5%) achieved a complete response and 12 (7.9%) a partial response leading to a global response of 87.4%. The 21-year overall survival is 82.6%; progression-free and disease-free survivals are 69.3% and 86.4%, respectively. Regarding the role of radiotherapy (RT), patients with a negative PET scan after MACOP-B did not undergo RT: One out of these 48 (2.1%) showed a relapse at 11 months. All relapsed/refractory patients who achieved a response with checkpoint inhibitors are still in continuous complete response with a median follow-up of 14 months. Data that we have gathered over a 30-year experience in the treatment of primary mediastinal B cell lymphoma patients clearly indicate that a third-generation chemotherapy regimen such as MACOP-B is feasible and easily deliverable on an outpatient basis. Regarding the unmet medical need of relapsed/refractory patients, new encouraging results occurred with the advent of the checkpoint inhibitors.

The treatment of hairy cell leukemia with a focus on long lasting responses to cladribine: A 30-year experience.

The treatment of hairy cell leukemia (HCL) has considerably changed over years. Purine analogues, namely cladribine, now represent the treatment of choice. One hundred and eighty-four patients were followed between 1986 and 2018 and treated according to era-specific guidelines. Responses were classified by combining Consensus Resolution criteria and marrow immunohistochemistry. Patients were grouped according to the number of treatment lines they received. Patients treated first line responded in 86% of cases, with complete response (CR) in 44% of cases. Response rates remained high throughout the first four lines (84%, 81%, 79% for the second line onward, with CR in 38%, 37%, 15% of cases respectively). One hundred and twenty-two patients received cladribine as first line treatment, with a response rate of 86% and a CR rate of 54%. Among the 66 CR patients, 45 (68%) have never received further therapy: 11 patients are in continuous CR between 5 and 10 years after treatment, 14 between 10 and 20 years and three patients at more than 20 years. Median time-to-next treatment (TTNT) for frontline cladribine-treated patients was 8.2 years: partial responders had a significantly shorter median TTNT than CR patients (5.3 years vs median not reached at 25.8 years, p < 0.001). Patients with HCL require subsequent lines of therapy in more than 50% of cases. Purine analogues allow significant response rates when applied first line and upon retreatment. Some patients may enjoy long lasting treatment-free intervals after one course of cladribine.

Diagnostic accuracy of positron emission tomography/computed tomography-driven biopsy for the diagnosis of lymphoma.

INTRODUCTION: Biopsy of affected tissue is required for lymphoma diagnosis and to plan treatment. Open incisional biopsy is traditionally the method of choice. Nevertheless, it requires hospitalization, availability of an operating room, and sometimes general anesthesia, and it is associated with several drawbacks. Fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) can be potentially used to drive biopsy to the most metabolically active area within a lymph node or extranodal masses. METHODS: A study of diagnostic accuracy was conducted to assess the performance of a PET-driven needle biopsy in patients with suspect active lymphoma. RESULTS: Overall, 99 procedures have been performed: three (3.0%) were interrupted because of pain but were successfully repeated in two cases. Median SUVmax of target lesions was 10.7. In 84/96 cases, the tissue was considered adequate to formulate a diagnosis (diagnostic yield of 87.5%) and to guide the following clinical decision. The target specimen was a lymph node in 60 cases and an extranodal site in 36. No serious adverse events occurred. The sensitivity of this procedure was 96%, with a specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 75%. CONCLUSION: Patients can benefit from a minimally invasive procedure which allows a timely and accurate diagnosis of lymphoma at onset or relapse.

Potential survival benefit for patients receiving autologous hematopoietic stem cell transplantation after checkpoint inhibitors for relapsed/refractory Hodgkin lymphoma: A real-life experience.

In recent years, novel drugs are available for the patients with relapsed/refractory Hodgkin lymphoma (HL), like immune checkpoint inhibitors (CPi). These drugs have been able to rescue a cohort of patients who subsequently could receive an allogeneic stem-cell transplant (SCT). No data were reported for subsequent autologous SCT (ASCT) after CPi. Here, we report our real-life experience in heavily pretreated HL patients undergoing ASCT as consolidation approach after CPi treatment. A retrospective observational study was conducted. Patients had CPi therapy in the context of clinical trials (n = 6) or in the named patient program (n = 7) between July 2014 and November 2019: 9 out of 13 received pembrolizumab and the remaining four underwent nivolumab. A median of 12 cycles (range, 3-16) of CPi therapy were infused. Thirteen patients underwent ASCT after CPi: 11 (84.6%) patients obtained a complete response (CR) and 2 had progression of disease, with an overall response rate of 84.6%. With a median follow-up of 3.3 years (range, 1.1-5.5), only one CR patient had disease relapse after 3.9 months from ASCT, leading to an estimated disease-free survival of 87.5% at 56.9 months. The estimated 5-year progression-free survival was 73.4% and overall survival was 92.3% at 4.8 years, respectively. No unexpected or cumulative toxicity was observed. Our results indicated that ASCT may represent a further effective therapeutic option as consolidation in HL after CPi treatment that today represents the last conventionally recognized therapeutic line.

Bendamustine-rituximab regimen in untreated indolent marginal zone lymphoma: experience on 65 patients.

First line therapy of patients with marginal zone lymphomas (MZL) is not well established and various regimens with chemo-immunotherapy can be used. Rituximab plus bendamustine (BR) is an effective and manageable treatment option for patients affected by indolent non-Hodgkin lymphoma. The aim of this monocentric retrospective study was to analyze the effectiveness and safety of the use of BR regimen in MZL patients in first line in daily clinical practice. The treatment schedule was rituximab at the dose of 375 mg/m2 on day 1 of each cycle and bendamustine at the dose of 90 mg/m2 on day 2 and 3, every 28 days for a maximum of 6 cycles. We analyzed 65 MZL patients (28 extranodal [EMZL], 23 splenic [SMZL], and 14 nodal [NMZL]) who underwent BR regimen as first line treatment. The median time from diagnosis to therapy was 2.5 months. Final responses were: 38 complete response (CR, 58.5%), 20 partial response and 7 progressive disease, leading to an overall response rate (ORR) of 89.2%. With respect to the histology, the ORR was 89.3% for EMZL, 82.6% for SMZL and 100% for NMZL, respectively (difference not statistically significant). With a median follow-up time of 44.6 months (range, 3.3-175.0 months), 2 (one EMZL after 42 months and one SMZL after 10 months) of 38 (5.2%) CR patients had disease relapse, yielding an estimated disease free survival of 89.2% at 61.1 months. The estimated 6-year progression free survival was 71.8% with 15 relapsed/progressed patients showing lymphoma recurrence within 48 months from end of treatment. The most frequently reported adverse events (any grade) were neutropenia (N = 35, 53.8%), fatigue (N = 15, 23.0%), and nausea (N = 12, 18.4%). All toxicities quickly resolved and no treatment-related death occurred. The BR regimen is effective and feasible in MZL patients inducing prolonged disease control with manageable toxicities.

Elderly Non-GCB Diffuse Large B-Cell Lymphoma Patient Responding to Lenalidomide after Epicardial Relapse: A Case Report.

There is an unmet clinical need for elderly or unfit diffuse large B-cell lymphoma (DLBCL) patients ineligible for autologous stem cell transplantation. Lenalidomide is an immunomodulatory agent with antitumor activity in non-Hodgkin lymphoma, with an acceptable toxicity profile and manageable side effects. A 79-year-old Caucasian male with non-germinal center B-cell-like DLBCL achieved complete remission (CR) after first-line treatment with seven out of eight scheduled cycles of a polychemotherapy containing anthracycline, which had to be discontinued early due to the onset of atrial fibrillation. After 5 months, the patient had an early epicardial relapse. He underwent lenalidomide considering age, cardiological comorbidities, and chronic renal failure. After the third cycle, he achieved CR, confirmed at restaging after the sixth cycle of treatment. Lenalidomide was safe and well tolerated in a patient with atrial fibrillation developed after an anthracycline-based regimen and a relapse of the DLBCL. Moreover, this regimen was effective in a case with a rare extranodal involvement of the epicardium.

Lenalidomide in Pretreated Patients with Diffuse Large B-Cell Lymphoma: An Italian Observational Multicenter Retrospective Study in Daily Clinical Practice.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma subtype, and approximately 50% of the patients are >60 years of age. Patients with relapsed/refractory (rr) disease have a poor prognosis with currently available treatments. Lenalidomide is available in Italy for patients with rrDLBCL based on a local disposition of the Italian Drug Agency. SUBJECTS, MATERIALS, AND METHODS: An observational retrospective study was conducted in 24 Italian hematology centers with the aim to improve information on effectiveness and safety of lenalidomide use for rrDLBCL in real practice. RESULTS: One hundred fifty-three patients received lenalidomide for 21/28 days with a median of four cycles. At the end of therapy, there were 36 complete responses (23.5%) and 9 partial responses with an overall response rate (ORR) of 29.4%. In the elderly (>65 years) subset, the ORR was 33.6%. With a median follow-up of 36 months, median overall survival was reached at 12 months and median disease-free survival was not reached at 62 months. At the latest available follow-up, 29 patients are still in response out of therapy. Median progression-free survivals differ significantly according to age (2.5 months vs. 9.5 in the younger vs. elderly group, respectively) and to disease status at the latest previous therapy (15 months for relapsed patients vs. 3.5 for refractory subjects). Toxicities were manageable, even if 30 of them led to an early drug discontinuation. CONCLUSION: Lenalidomide therapy for patients with rrDLBCL is effective and tolerable even in a real-life context, especially for elderly patients. IMPLICATIONS FOR PRACTICE: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma, and approximately 50% of the patients are >60 years of age. Patients with relapsed/refractory (rr) disease have a poor prognosis, reflected by the remarkably short life expectancy of 12 months with currently available treatments. The rrDLBCL therapeutic algorithm is not so well established because data in the everyday clinical practice are still poor. Lenalidomide for patients with rrDLBCL is effective and tolerable even in a real-life context, especially for elderly patients.

Spontaneous remission of follicular lymphoma.

Follicular lymphoma is an indolent B cells proliferative disorder that represents approximately 35% of all non-Hodgkin lymphomas. Although spontaneous remission is uncommon in patients with low grade non-Hodgkin lymphomas, some cases have been reported. We present a case of follicular lymphoma for which we have documented a spontaneous remission both with serial instrumental investigations and through histological biopsy of the bone marrow. The patient is still in remission after 2 years of follow-up. The causes for a spontaneous remission are not known, and we can only hypothesize a possible reawakening of the host's immune response against the tumour.

A case report of the long treatment experience of a Sézary syndrome responder patient: 16 years through all the systemic and innovative therapies.

Existing therapies for Sézary syndrome (SS) are limited in efficacy and in disease control, and patients have very poor prognosis. Here, we report a case report of a patient who has a 16-year history of SS and related treatments (both standard and experimental). In particular, two drugs, one conventional (gemcitabine) and one experimental (mogamulizumab), were able to induce long lasting response. Patient refused to undergo allogeneic stem cell transplantation. After eleven lines of therapeutic approaches, the patient is in very good partial response and free of therapy at the latest available follow-up.

Lenalidomide in Pretreated Mantle Cell Lymphoma Patients: An Italian Observational Multicenter Retrospective Study in Daily Clinical Practice (the Lenamant Study).

BACKGROUND: Mantle cell lymphoma (MCL) has the worst prognosis of B-cell subtypes owing to its aggressive clinical disease course and incurability with standard chemo-immunotherapy. Options for relapsed MCL are limited, although several single agents have been studied. Lenalidomide is available in Italy for patients with MCL based on a local disposition of the Italian Drug Agency. SUBJECTS, MATERIALS, AND METHODS: An observational retrospective study was conducted in 24 Italian hematology centers with the aim to improve information on effectiveness and safety of lenalidomide use in real practice. RESULTS: Seventy patients received lenalidomide for 21/28 days with a median of eight cycles. At the end of therapy, there were 22 complete responses (31.4%), 11 partial responses, 6 stable diseases, and 31 progressions, with an overall response rate of 47.1%. Eighteen patients (22.9%) received lenalidomide in combination with either dexamethasone (n = 13) or rituximab (n = 5). Median overall survival (OS) was reached at 33 months and median disease-free survival (DFS) at 20 months: 14/22 patients are in continuous complete response with a median of 26 months. Patients who received lenalidomide alone were compared with patients who received lenalidomide in combination: OS and DFS did not differ. Progression-free survivals are significantly different: at 56 months, 36% in the combination group versus 13% in patients who received lenalidomide alone. Toxicities were manageable, even if 17 of them led to an early drug discontinuation. CONCLUSION: Lenalidomide therapy for relapsed MCL patients is effective and tolerable even in a real-life context. IMPLICATION FOR PRACTICE: Several factors influence treatment choice in relapsed/refractory mantle cell lymphoma (rrMCL), and the therapeutic scenario is continuously evolving. In fact, rrMCL became the first lymphoma for which four novel agents have been approved: temsirolimus, lenalidomide, ibrutinib, and bortezomib. The rrMCL therapeutic algorithm is not so well established because data in the everyday clinical practice are still poor. Lenalidomide for rrMCL patients is effective and tolerable even in a real-life context.

A patient with plasmablastic lymphoma achieving long-term complete remission after thalidomide-dexamethasone induction and double autologous stem cell transplantation: a case report.

BACKGROUND: No standard of care is established for plasmablastic lymphoma (PBL) and prognosis remains extremely poor, given that patients relapse early after chemotherapy and display resistance to commonly applied cytostatic drugs. CASE PRESENTATION: We report a case of nodal, HIV-unrelated PBL in a patient who achieved and maintained a very long lasting complete remission after an intensive therapy consisting consisting of thalidomide plus dexamethasone followed by a consolidation with double autologous stem cell transplantation. Our approach was based on the full application of a standard multiple myeloma treatment and, to the best of our knowledge, it represents the only reported experience so far. This treatment was overall well tolerated. CONCLUSIONS: Multiple myeloma-like treatment may represent a possible alternative to intensive lymphoma-directed therapies.

Efficacy and safety of biosimilar epoetin alpha in patients with chronic lymphoid neoplasms and chemotherapy-induced anaemia: An observational, retrospective, monocentric analysis.

Epoetin biosimilars are an alternative to originator erythropoietic agents in the treatment of chemotherapy-induced anaemia; however, their effects in patients with lymphoproliferative disorders remain unclear. This analysis examined the response of patients with lymphoproliferative disorders experiencing chemotherapy-induced anaemia to 4- or 8-week treatment with the biosimilar epoetin alpha. Treatment was initiated at first occurrence of haemoglobin (Hb) < 10 g/dL during chemotherapy and was stopped when Hb was >11 g/dL, when chemotherapy was completed, or in case of transfusion dependency. Response to epoetin alpha was defined as an increase in Hb of >1 g/dL or as an Hb > 11 g/dL. Stability was defined as change in Hb of ±1 g/dL, and no response was indicated by a decrease in Hb of >1 g/dL or acquired transfusion dependence. Overall, 65 patients were enrolled (median age 69 years; 47.7% ≥ 70 years old). Mean Hb levels at the initiation of epoetin alpha was 9.3 ± 0.5 g/dL. Mean Hb levels reached 10.7 ± 1.4 and 10.6 ± 1.5 g/dL at weeks 4 and 8, respectively, in patients on first-line chemotherapy and 11.4 ± 1.6 and 9.7 ± 1.3 g/dL in those on a second- or higher-line regimen. Overall, 70.8% of patients responded, 26.1% had stable Hb, and 3.1% did not respond. Delays or interruption of any chemotherapy cycle due to anaemia occurred in 18 patients. The biosimilar epoetin alpha was well tolerated and allowed patients with non-Hodgkin lymphoma or chronic lymphoproliferative disorders to continue their course of chemotherapy by effectively increasing and maintaining adequate concentrations of Hb.