Issues for Blood Management in Hematology/Oncology

Hematology/Oncology patients comprise a unique subpopulation for whom transfusion therapy is often necessary in both the acute care setting as well as for long-term support. Red blood cells (RBCs) and platelets are the most common components transfused particularly in patients undergoing high-dose chemotherapy, intensive radiation therapy and human hematopoietic stem cell transplantation (HSCT).

Restrictive transfusion practice has become the “new world order” particularly for general medical and surgical patients. Those with hematologic malignancies or solid tumors have not frequently been a large part of many of the randomized controlled trials that speak to this approach. Literature is available, however, that provides evidence that judicious use of blood components via restrictive transfusion and single unit transfusions for inpatients and outpatients can be clinically effective, safe, and will decrease the potential for transfusion-associated adverse events.

Feasibility studies of restrictive RBC transfusion in the Hematology/Oncology population have been reported. These studies provide compelling evidence that lower transfusion triggers, targets and single unit use are not associated with increased bleeding episodes and will reduce overall transfusion exposure.¹ ² ³ The American Society of Hematology (ASH), as part of their Choosing Wisely Campaign, advises against liberal transfusion of RBCs with hemoglobin (Hgb) targets of 7- 8 g/dL, along with implementation of single-unit transfusions when possible.4

Recent RCTs and consensus from the AABB point to similar restrictive practice for platelet transfusion with a trigger of 10,000/µL for prophylactic transfusion in most patients.⁵ Subgroups of patients, such as those with autologous HSCTs, may not require prophylactic transfusion at this level, but can be effectively transfused using a therapeutic-only strategy.⁶ The use of lower doses of platelets has been shown to be safe and effective.⁷ Similar strategies may also be applicable for outpatients.⁸

Pursuant to those patients receiving radiation therapy, historically, there have been reports in the literature that found loco-regional control to be improved in patients whose Hgb is maintained at a higher level, typically > 10 g/dL. Many, if not most of these studies had significant confounding and have not adjusted for comorbidities. A publication in 2012, however, concluded “…that hypoxia is a well-established cause of radio-resistance, but modification of this cannot be achieved by correcting low Hgb levels by…transfusion and/or [ESAs[.”⁹ Similarly, a recent study covering over 30 years of experience with cervical cancer patients undergoing radiation therapy (the original target population from a historical perspective) adjusted for confounders and found no evidence that anemia represented an independent predictor of outcomes associated with diagnosis or treatment. ¹° Transfusion, in and of itself, has significant negative immunomodulatory effects via cell-to-cell interactions and cytokines.   Thus, maintenance of Hgb levels for these patients should not be considered an absolute necessity.

Other interventions may prove successful for Hematology/Oncology patients as part of a Blood Management Program. Identification and treatment of concomitant iron deficiency anemia or other nutritional deficiencies can potentially decrease or eliminate the need for transfusion. Drugs that might increase the risk for bleeding or hemolysis should be eliminated if possible as these cause or potentiate anemia. Use of new targeted drugs such as lenalidomide in patients with 5q deletion-associated MDS may prevent the need for long-term transfusion dependence. The use of antifibrinolytics in patients who have become refractory to platelet transfusions can enable platelet function even at low levels and prevent the unnecessary use of limited platelet resources.

Outpatient transfusion in the Hematology/Oncology arena comes with some unique circumstances. Many outpatients remain stable and will be capable of lower transfusion thresholds and longer intervals for both RBCs and platelets. Evidence-based restrictive transfusion can and should be a part of outpatient treatment strategy, just as with inpatients if the accessibility to post-transfusion care is adequate. No national guidelines are available for outpatient transfusion and each patient scenario must be considered on an individual basis, but certainly the absolute need for “standing” transfusions and obligatory 2-unit transfusions should be discouraged. Consider, as well, that patients often have their own view of the “need” for transfusion when symptoms and signs do not necessarily make it requisite. Discussion with our patients is essential to allow them to understand transfusion decisions.

The risks of transfusion are both immediate and delayed, particularly for those with chronic transfusion needs. Febrile non-hemolytic, allergic, hemolytic reactions, TRALI and TACO may occur as in other patient populations and should be recognized and treated as appropriate. Alloimmunization and transfusion-related iron overload are more common in the Hem/Onc arena given the potential for increased component exposure during the acute care setting and the high percentage of those that necessitate chronic transfusion support. The potential for transfusion-associated graft vs. host disease is also more worrisome given the degree of immunosuppression in these patients. Specialized products are often necessary including leukoreduced, antigen negative, irradiated or HLA-matched components. These specialized products may not be available on a STAT basis and add significantly to the overall transfusion cost. Careful consideration is warranted and inclusion of the Transfusion Service is key.

In the end, transfusion practice for Hematology/Oncology patients should include restrictive transfusion practices with assessment of the risks and benefits at the time of each potential transfusion episode. Each patient, whether inpatient or outpatient, should be evaluated based on their current state of stability, clinical course and availability and access to care. Nutritional assessments and subsequent interventions along with pharmaceutical agents may provide additional ways by which transfusion exposure can be decreased. Special products are often necessary and needs should be discussed with the Transfusion Service. Limiting transfusion ultimately avoids unpleasant, potentially severe acute and delayed adverse events as well as preserving resources within our communities.

References:

  1. Jansen et al. Transfus Med 2004; 14: 33
  2. Berger et al. Haematologica 2012; 97: 116
  3. Webert et al. Transfus 2008; 48: 81
  4. choosingwisely.com
  5. Kaufman et al. Ann Intern Med 2014; doi: 10.7326/M14-1589
  6. Stanworth et al. Transfus 2014; 54: 2385
  7. Slichter et al. N Engl J Med 2010; 362: 600
  8. Sagmeister et al. Blood 1999; 93: 3124
  9. Hoff Acta Oncologica 2012; doi: 10.3109/0284186X.2011.653438
  10. Bishop et al. Int J Radiat Oncol Biol Phys 2014; doi: 10.1016/j.ijrobp.2014.09.023

Burns

-Dr. Burns was a private practice pathologist, and Medical Director for the Jewish Hospital Healthcare System in Louisville, KY. for 20 years. She has practiced both surgical and clinical pathology and has been an Assistant Clinical Professor at the University of Louisville. She is currently available for consulting in Patient Blood Management and Transfusion Medicine. You can reach her at cburnspbm@gmail.com.

Pancytopenia in a 67-Year-Old Female

A 67-year-old female presents with pancytopenia, a markedly enlarged spleen, and extramedullary hematopoiesis. Her blood smear is shown here. She is found to have a JAK-2 mutation. What is the diagnosis?

myeloprolif

  1. Chronic myelofibrosis
  2. Chronic myeloid leukemia
  3. Hairy cell leukemia
  4. Metastatic breast carcinoma
  5. Renal cell carcinoma

The diagnosis in this case is chronic myelofibrosis. Chronic myelofibrosis is one of the four main chronic myeloproliferative disorders (the others are chronic myeloid leukemia, essential thrombocythemia, and polycythemia vera). In this disorder, the bone marrow is initially hypercellular, with proliferation of all of the myeloid cell lines (neutrophils, red cells, and megakaryoblasts). Over time, however, the marrow becomes progressively fibrotic. Eventually, there is not enough room for normal hematopoiesis, and the body starts making hematopoietic cells elsewhere (most notably in the spleen, which becomes markedly enlarged).

In these later stages of chronic myelofibrosis, the blood is characterized by pancytopenia (a decrease in white cells, red cells and platelets). Teardrop-shaped red cells (dacryocytes) may also be seen as a result of the red cells wending their way through a fibrotic marrow. Red cell precursors, such as the normoblast present in this image, are also commonly present, as there is less and less room for red cells to mature fully before leaving the marrow.

These blood smear findings are not specific for chronic myelofibrosis. Teardrop-shaped red cells may be seen when the marrow is fibrotic for other reasons, such as metastatic cancer, and pancytopenia and normoblasts may be seen in many other conditions. The JAK-2 mutation, however, is seen most frequently in three of the four chronic myeloproliferative disorders: polycythemia vera, essential thrombocythemia, and chronic myelofibrosis.

Krafts

-Kristine Krafts, MD, is an Assistant Professor of Pathology at the University of Minnesota School of Medicine and School of Dentistry and the founder of the educational website Pathology Student.

A Rare Myeloproliferative Disorder

hypereosinophilic

A 59-year-old male presents with skin lesions, hepatosplenomegaly and cardiomyopathy. A representative field of his blood smear is shown here. Of the following, what is the most likely diagnosis?

  • A. Chronic myeloid leukemia
  • B. Multiple myeloma
  • C. Metastatic prostate carcinoma
  • D. Hypereosinophilic syndrome
  • E. Bacterial sepsis

The diagnosis in this case is hypereosinophilic syndrome, a rare myeloproliferative disorder characterized by a marked and persistent elevation in the eosinophil count. Although this disease is primarily a hematopoietic disorder, it usually affects many other organ systems, such as the cardiovascular, nervous, respiratory, and gastrointestinal systems. Typical presenting symptoms include cardiomyopathy, skin lesions, thromboembolic disease, neuropathy, hepatosplenomegaly, and pulmonary disease. The pathophysiology behind the damage in these organs isn’t well understood, but it probably has something to do with the release of eosinophil granules in those tissues.

You need to have three things in order to make the diagnosis:
1. Persistent eosinophilia (absolute eosinophil count >1500/μL)
2. No other cause for the eosinophilia
3. Signs and symptoms of organ involvement

Other more common causes of eosinophilia, such as drug reactions, allergic reactions and autoimmune disease, must be ruled out before making the diagnosis.

Usually, patients aren’t treated unless or until they have symptoms (because the treatment itself has its risks). These patients are monitored closely with serum troponin levels (to monitor for MI), echocardiograms and pulmonary function tests.

Some patients with hypereosinophilic syndrome have a tiny deletion in 4q12, which ends up producing a fusion transcript called FIP1LI-PDGFRA (which is also present in some cases of systemic mastocytosis). Imatinib works very well in the majority of these patients.

Patients who have symptoms (but not FIP1LI-PDGFRA) are generally treated with steroids first. If those don’t work, interferon alpha and hydroxyurea are used. If those don’t work either, then imatinib is the treatment of choice (it doesn’t work as well as it does in patients withFIP1LI-PDGFRA, but it does seem to work in at least some of these patients).

Here are the reasons the other answers are incorrect.

  1. Myeloma is a monoclonal disease of plasma cells which manifests mainly in the bone marrow. In the blood, the main thing you see is rouleaux (red cells stacking up on top of each other). This blood smear just has a lot of eosinophils – so it’s not consistent at all with myeloma. The clinical history also doesn’t fit. In myeloma, patients usually have bone pain, signs of anemia (fatigue, palpitations), and maybe signs of renal failure. Hepatosplenomegaly, skin lesions, and cardiomyopathy aren’t generally seen in myeloma.
  2. In CML, you see a massive leukocytosis which is composed of neutrophils and precursors. There is a big left shift and a basophilia. This smear just has a ton of eosinophils, which is not consistent with CML. The patient’s hepatosplenomegaly would be consistent with CML (especially the splenomegaly part) – but the skin lesions and cardiomyopathy don’t go along with that diagnosis.
  3. In metastatic prostate cancer, it’s possible that you might see a rare tumor cell in the blood; you might also see a monocytosis (you occasionally can see that with solid tumors). Eosinophilia, however, is not consistent with prostate cancer. The history is also unsupportive. Patients with advanced prostate cancer may have urinary symptoms (trouble urinating, blood in the urine), abdominal or pelvic pain, or signs of metastasis (bone pain, particularly in the spine).
  4. The characteristic blood finding in bacterial sepsis is a neutrophilia, with or without a left shift. You may also see toxic changes in the neutrophils: toxic granulation, Döhle bodies, and/or cytoplasmic vacuolization. Bacterial infections generally don’t produce an eosinophilia – but some parasitic infections can.

Krafts

-Kristine Krafts, MD, is an Assistant Professor of Pathology at the University of Minnesota School of Medicine and School of Dentistry and the founder of the educational website Pathology Student.

You Make the Diagnosis

A 42-year-old male presents with fever and fatigue. A CBC shows the following:

Hgb 14.2 g/dL (normal = 13.5 – 17.5 g/dL)
WBC 18 x 109/L (normal = 4.5 – 11 x 109/L)
Platelet count 320 x 109/L (normal = 150 – 450 x 109/L)

Differential:

  • Neutrophils and precursors: 80%
  • Lymphocytes: 16%
  • Monocytes: 2.5%
  • Eosinophils: 1.4%
  • Basophils: 0.1%

A review of the blood smear shows a slight left shift in the neutrophil series, with occasional metamyelocytes and rare myelocytes present. Several cells similar to the one shown below are noted.

toxic-gran

Which of the following is the most likely diagnosis?

A.  Acute myeloid leukemia
B. Chronic myeloid leukemia
C. Bacterial infection
D. Viral infection
E. Parasitic infection

The answer in this case is C, bacterial infection. The cell shown in the photo is a slightly immature neutrophil showing toxic granulation (heavy, dark azurophilic cytoplasmic granules), a morphologic sign seen most commonly in severe bacterial infections. The elevated neutrophil count with a left shift supports the diagnosis of bacterial infection.

Toxic granulation is thought to be a result of the bone marrow’s response to the need for neutrophils in the peripheral tissues. Promyelocytes are the last dividing stage of the neutrophil series (once a cell reaches the myelocyte stage, it can no longer divide, but only mature). Normally, as promyelocytes divide, their azurophilic granules are dispersed into daughter cells, the end result being a mature neutrophil with few azurophilic granules.

If there is an urgent need for increased numbers of neutrophils, like there is in a severe bacterial infection, promyelocytes may opt to simply mature, rather than divide. As a result, the azurophilic granules are not diluted among daughter cells, but retained in the maturing neutrophil, the end result being a mature neutrophil with many more azurophilic granules than usual.

The normal red cell and platelet count, as well as the lack of a significant number of very immature myeloid cells, rules out the presence of acute myeloid leukemia (AML). In AML, at least 20% of the nucleated cells in the blood or bone marrow must be composed of blast or blast equivalents.

Chronic myeloid leukemia (CML) is often a consideration in patients with an elevated neutrophil count and a left shift. In CML, however, the neutrophil count is usually quite high, and there is a marked left shift, with a particularly large number of myelocytes. In addition, a basophilia is almost always present.

Viral infection often presents with a lymphocytosis, sometimes with reactive changes in the lymphocytes. Finally, some parasitic infections present with an eosinophilia (but not a neutrophilia).

 

Krafts

-Kristine Krafts, MD, is an Assistant Professor of Pathology at the University of Minnesota School of Medicine and School of Dentistry and the founder of the educational website Pathology Student.

Name That Cytogenetic Abnormality

A 36-year-old male presents with recurrent epistaxis and fatigue of several days’ duration. Physical examination reveals numerous ecchymoses scattered over his limbs and trunk. A CBC shows the following:

  • Hgb 9.2 g/dL (normal = 13.5 – 17.5 g/dL)
  • WBC 31×109/L (normal = 4.5 – 11 x 109/L)
  • Platelet count 23 x 109/L (normal = 150 – 450 x 109/L)

Review of the blood smear shows numerous hypergranulated immature myeloid cells. Rare cells like the cell below are also present.

auer-rod

What cytogenetic abnormality is most likely present in the abnormal cells?

  1. inv(16)
  2. t(8;21)
  3. t(14;18)
  4. t(15;17)
  5. t(11;14)

The answer is D, t(15;17). This is a case of acute promyelocytic leukemia (or AML-M3 in the old FAB classification). The key to the diagnosis is the cell in the image above, which is an immature myeloid cell containing innumerable Auer rods. This cell is called a faggot cell because the Auer rods resemble a bundle of sticks (or faggot). Faggot cells are specific for acute promyelocytic leukemia; they are not seen in any other hematologic malignancy.

Other clues to the diagnosis which are not entirely specific for acute promyelocytic leukemia include the anemia and thrombocytopenia (which point towards bone marrow failure), and the leukocytosis (which presumably is comprised mostly of the hypergranular myeloid cells noted on the blood smear).

Acute promyelocytic leukemia (APL) is a type of acute leukemia in which the predominant cell type is the promyelocyte. The malignant promyelocytes in APL have a distinctive appearance which is different from that of normal promyelocytes. In most cases, the malignant promyelocytes in APL contain innumerable small azurophilic granules – but in rare cases, the promyelocytes are hypogranular.

The characteristic morphologic finding in APL is the faggot cell, as shown above. When you see faggot cells, you can make the diagnosis of APL based on morphology alone, without waiting for molecular or cytogenetic studies (which will show the characteristic t(15;17) of APL – but which take some time to perform).

Making an immediate, morphologic diagnosis is critical in cases of APL, because patients with APL cannot be given routine acute myeloid leukemia chemotherapeutic agents. The granules in the malignant promyelocytes contain substances which quickly activate the coagulation system. Traditional chemotherapeutic agents cause cell lysis and release of the procoagulant substances, which puts the patient at high risk for disseminated intravascular coagulation (DIC).

Patients with APL are given a drug called all-trans retinoic acid (ATRA) that overcomes the maturation block caused by the translocation between chromosomes 15 and 17. Following ATRA therapy, the malignant promyelocytes mature into segmented neutrophils, and the risk of DIC diminishes.

The other cytogenetic translocations in this question are seen in different disorders: inv(16) is seen in some cases of acute myelomonocytic leukemia (AML-M4); t(8;21) is seen in some cases of acute myeloblastic leukemia with maturation (AML-M2); t(14;18) is seen in follicular lymphoma; and t(11;14) is seen in mantle cell lymphoma.

Krafts

-Kristine Krafts, MD, is an Assistant Professor of Pathology at the University of Minnesota School of Medicine and School of Dentistry and the founder of the educational website Pathology Student.

Heparin-Induced Thrombocytopenia

The fine folks over at The Poison Review discuss a paper about heparin-induced thrombocytopenia that is relevant to your interests. The paper appeared in the journal Clinical Toxicology and is geared toward that audience, but even so it serves as a nice refresher for technologists working in coagulation and hematology.