Hematology oncology



LMW heparin, including dalteparin (Fragmin) and enoxaparin (Lovenox)

• Standard of care for acute DVT (inpt or outpt) and mild/moderate pulmonary embolism (inpatient only for enoxaparin; off label but accepted use for dalteparin).

• Contraindications: significant renal failure, recent lumbar puncture, spinal instrumentation, need for invasive procedures, and extremes of weight (100 kg)

• Dosing for DVT/PE treatment (full anticoagulation)

– Dalteparin 100 IU/kg sc q12 hrs

– Enoxaparin 1 mg/kg sc q12 hrs

• Monitoring only indicated in modest renal failure, pregnancy, and wt 100 kg.

– Monitor with anti-Xa level drawn 4 hrs after 1st or 2nd dose; goal anti-Xa level is 0.5-0.85.

• T½ 4 hrs. Duration of anticoagulation 12-24 hrs.

• Pharmacologic reversal is difficult; protamine reverses only about 50% of the activity but can be given for serious bleeding.

• Type II HIT is less common than with unfractionated heparin.

• Do not use in patients with known HIT.

Heparin, unfractionated

• Alternative to LMWH for treating DVT/PE (e.g. in settings of renal failure, extremes of weight, pending invasive procedure).

• Goal PTT 60-85. Must be therapeutic within 24 hrs.

• Check PTT at 6 hrs after start and every rate change; BID only when therapeutic.

• T½ 90 minutes.

• Coagulation normalized 6 hrs after discontinuation.

• Acute reversal, give protamine 20 mg/min iv, no more than 50 mg over 10 min (about protamine 1 mg neutralizes heparin 100 U; need to take account half life of heparin)

• Heparin-induced thrombocytopenia (HIT): avoid all heparin in type II, including flushes

– Type I: platelet drop first 48 hrs, but plts > 100K; HIT Ab negative; no thrombosis risk

– Type II: platelet drop at 5-10 days, 2.5X, decrease infusion 50%

– Recheck PTT 4 hrs after any change or at least once per day

• Renal failure requires significant dosage adjustment (consider argatroban instead):

– Bolus 0.2 mg/kg IVP, then

– CrCl 45-60: decrease infusion rate to 50% (0.075 mg/kg/hr)

– CrCl 30-44: decrease infusion rate to 30% (0.045 mg/kg/hr)

– CrCl 15-29: decrease infusion rate to 15% (0.0225 mg/kg/hr)

– CrCl 6.

Warfarin

• Indicated for long-term oral anticoagulation.

• Starting dose 5 mg po qhs x 2-3 days, then per INR.

• Goal INR usually 2-3 for DVT/PE, TIA, or atrial fibrillation

– Higher for mechanical valves (see section on anticoagulation for prosthetic valves).

• Overlap with LMWH, heparin, or thrombin inhibitors required for 5 days, with 2 days after INR >2

– INR will increase with decreased factor VII but antithrombosis does not occur until factor II is depleted by warfarin, which requires approximately 5 days.

• T½ 40 hrs but highly variable depending on many drug interactions (e.g. digoxin, amiodarone).

• Reversal

– FFP, immediate but transient effect (lasts about 6 hrs).

– Vitamin K, 5 mg sc or po x 3 days; with normal liver function, reversal should begin within about 12 hrs.

– Recombinant activated factor VII, evolving use (see Ann Intern Med 2002;137:884)

Starting warfarin in patients on direct thrombin inhibitors

• Direct thrombin inhibitors affect the INR as well as the PTT, obscuring the effect of warfarin.

• Overlap for at least 5 days, as with heparin.

• Two monitoring alternatives:

– Chromogenic factor X level to assess the effect of warfarin (see box).

– Stop the thrombin inhibitor infusion for 3 hrs and check the INR and PTT. Then resume the infusion if INR not therapeutic.

Tumor lysis syndrome

BACKGROUND

• Generally seen when effective chemotherapy is initiated against hematologic malignancies that are rapidly growing or large volume, but can also occur spontaneously.

Etiologies

• Acute leukemias.

• Intermediate- or high-grade lymphomas: Burkitt’s, lymphoblastic, diffuse large cell.

• Risk is higher with bulky tumor masses, markedly elevated LDH or white count, or pre-existing renal failure.

• Rarely seen with solid tumors.

Helpful studies and laboratory information

• The diagnostic laboratory test is a rising or elevated uric acid level plus:

– Hyperkalemia

– Hyperphosphatemia leading to hypocalcemia

– Oliguria leading to acute renal failure

Treatment

• The main goal is to prepare in advance to prevent complications—which are mostly due to hyperkalemia and uric acid-induced nephropathy.

• Start allopurinol 300-600 mg po qd 24-48 hrs in advance of chemotherapy if possible.

• Start D5W with 3 amps (150 mEq total) of NaHCO3 at 200-250 cc/hr up to 24 hrs in advance.

• Goal urine pH >8.0. Follow urine pH q 8-12 hrs.

• Keep urine output at 200 cc/hr and fluid balance even; furosemide if necessary.

• Check uric acid, electrolytes, BUN/Cr, Ca, P, Mg at least every 6-8 hrs.

• Fulminant disease may require dialysis for control of hyperkalemia.

Lactic acidosis

• LACTIC ACIDOSIS CAN OCCUR IN PATIENTS WITH MALIGNANCY WITHOUT EVIDENCE OF POOR TISSUE PERFUSION, PRESUMABLY DUE TO ANAEROBIC METABOLISM BY THE TUMOR CELLS.

• Rapidly progressive hematologic neoplasms, e.g. lymphoma, leukemia.

• Extensive hepatic metastases from solid tumors, e.g. small cell lung cancer.

• The only treatment is chemotherapy for the tumor and the prognosis is determined by the responsiveness of the tumor.

Spinal cord compression

BACKGROUND

• Strongly consider in any patient with a solid tumor and back pain

– Most common presenting complaint in patients with cord compression, prior to onset of neurologic deficits.

• Early diagnosis is critical because neurologic status at the start of treatment is the best predictor of neurologic status at the conclusion of treatment.

Etiologies

• Metastatic solid tumors, e.g. breast, lung, prostate, renal cell.

• Lymphoma or multiple myeloma.

Points to consider in evaluation

• Back pain, often localized vertebral or radicular pain.

• New onset of falls.

• Lower extremity weakness or sensory disturbance.

• Bowel or bladder dysfunction.

• Check for

– Lower extremity hyperreflexia,

– Positive Babinski sign

– LE weakness or sensory deficit,

– Spinal sensory level

– Decreased anal sphincter tone

– Gait ataxia

Helpful studies and laboratory information

• Order urgent spinal MRI with cord compression protocol. This protocol performs limited images of the entire spine, which is essential, as multiple sites of compression may be present.

• Thoracic sites are most common, followed by lumbosacral and then cervical.

Treatment

• Initiate dexamethasone 10 mg iv bolus, then 4 mg iv or po q6 hrs, immediately, if a patient with known metastatic tumor develops back pain and neurologic deficits.

• Once the diagnosis is established by MRI, prepare for emergent radiation therapy or surgical decompression (consult radiation oncology and/or neurosurgery and/or ortho spine).

General considerations

• Guidelines adapted from ID guidelines (authored by Dr. Jay Fishman).

• Fever defined as single oral temp to >101(F (38.3(C) or persistent temperature >100.4(F (38(C)

• Neutropenia defined as absolute neutrophil count 20 days).

• For those with risk factors for invasive fungal infection, consider early initiation of antifungal therapy.

• For those without risk factors, consider radiological workup with chest CT (to assess for early invasive aspergillosis) and abdomen CT ( to assess for hepatosplenic candidiasis).

– Aggressive pursuit of CT abnormalities (e.g. BAL or biopsy) highly encouraged in order to establish a microbiologic diagnosis.

Breast cancer

• AC – cyclophosphamide, Adriamycin (doxorubicin)

• CA – cyclophosphamide, Adriamycin

• CAF – cyclophosphamide, Adriamycin, 5-FU

• CMF – cyclophosphamide, methotrexate, 5-FU

• CEF – cyclophosphamide, epirubicin, 5-FU

• TAC – Taxol (paclitaxel), Adriamycin, cyclophosphamide

• Sequential AC/paclitaxel (Taxol)

• Paclitaxel/vinorelbine (Navelbine)

Colon cancer

• 5-FU + leucovorin

• 5-FU + leucovorin + irinotecan

• 5-FU + leucovorin + oxaliplatin

• Capecitabine (Xeloda)

Prostate cancer

• Antiandrogen therapy

• Mitoxantrone + prednisone

• Estramustine (EMP) + docetaxel

Pancreatic cancer

• Gemcitabine

Hepatocellular carcinoma

• PIAF – cisplatin, interferon-alpha, Adriamycin, 5-FU

Small cell lung cancer

• EP – etoposide, cisplatin

• CEV – cyclophosphamide, epirubicin, vincristine

• CAV – cyclophosphamide, Adriamycin, vincristine

• Irinotecan + cisplatin

Non-small cell lung cancer

• PE – cisplatin + etoposide

• PEI – cisplatin + etoposide + ifosfamide

• MVP – mitomycin, vindesine, cisplatin

• GC – gemcitabine + cisplatin

• PC – paclitaxel + carboplatin

Germ cell tumors

• BEP – bleomycin, etoposide, cisplatin

• PVB – cisplatin, vinblastine, bleomycin

• VIP – etoposide, ifosfamide, cisplatin

AML

• “7+3” – 7 days of cytarabine + idarubicin on the 1st 3 days as well for induction

• HiDAC – high dose cytarabine

• ADE – cytarabine, daunorubicin, etoposide

• ATRA – all trans retinoic acid (only for M3 type)

CML

• Interferon-alpha + cytarabine

• Imatinib (Gleevec)

CLL

• Fludarabine

• Cladribine

• Rituximab

• Alemtuzumab

Hodgkin’s disease

• ABVD – Adriamycin, bleomycin, vinblastine, dacarbazine

• MOPP – mustargen, Oncovin (vincristine), prednisone, procarbazine

• ESHAP – etoposide, Solu-Medrol, cytarabine, prednisone

• ICE – ifosfamide, carboplatin, etoposide

• EIP – etoposide, ifosfamide, cisplatin

Non-Hodgkin’s lymphoma

• CHOP – cyclophosphamide, hydroxydaunorubicin (Adriamycin), Oncovin (vincristine), prednisone

• CHOP-R – above + rituximab

• MOPP – mustargen, Oncovin (vincristine), prednisone, procarbazine

• ICE – ifosfamide, carboplatin, etoposide

• EPOCH – etoposide, prednisone, Oncovin (vincristine), cyclophosphamide, hydroxydaunorubicin (Adriamycin)

• DHAP – dexamethasone, cytarabine, cisplatin

Multiple myeloma

• Dexamethasone alone

• Thalidomide alone

• MP – melphalan, prednisone

• VAD – vincristine, Adriamycin, dexamethasone

• TD – thalidomide, dexamethasone

• Bortezomib (Velcade, PS 341)

Hairy cell leukemia

• Cladribine

Targeted and new therapies

• Anastrozole (Arimidex) – direct inhibiter of aromatase for breast cancer

• Trastuzumab (Herceptin) – anti-HER2/neu protein monoclonal antibody for breast cancer

• Rituximab (Rituxan) – anti-CD20 monoclonal antibody on B-cells

• Gemtuzumab ozogamicin (Mylotarg) – anti-CD33 monoclonal antibody for AML

• Alemtuzumab (Campath-1H) – anti-CD52 monoclonal antibody for CLL

• Cetuximab (Erbitux) – monoclonal antibody targeting epidermal growth factor

• Bevacizumab (Avastin) – monoclonal antibody targeting VEGF

• Gefitinib (Iressa) – specific target of EGFR TK domain for lung cancer

• Imatinab (Gleevec) – direct tyrosine kinase inhibitor in CML and GIST

• Bortezomib (Velcade) – proteosome inhibitor for treating multiple myeloma

• Capecitabine (Xeloda) – prodrug of 5-FU for breast and colon cancer

General considerations

• Stem cell transplants are used to treat many conditions. Most common among them are the leukemias, lymphomas, multiple myeloma, aplastic anemia, and myelodysplastic syndrome. Less common indications include thallasemias, sickle cell disease, and autoimmune diseases.

• “Hematopoietic stem cell transplantation” (HSCT) is a broader term than the previously used “bone marrow transplantation” (BMT), recognizing that there are multiple sources of stem cells for transplantation.

Sources of stem cells

• Bone marrow. Harvested from the posterior iliac crests. The minimum number of CD34+ cells from the marrow needed per transplant has not been well established, though approximately 10-15 cc of bone marrow per kilogram are harvested from the donor, which takes over 100 aspirates from the bone marrow to achieve.

• Peripheral blood stem cells (PBSC). Stem cell (CD34+) production and release into the periphery can be stimulated either by GM-CSF or G-CSF infusion, cytotoxic chemotherapy such as cyclophosphamide, or a combination of the two. PBSCs are then harvested by leukopheresis from the donor for transplantation. A minimum of 2 million CD34+ cells per kilogram to ensure reliable engraftment. Benefits of PBSCT over BMT include more rapid hematologic reconstitution, and improved quality of life. PBSCT are now the standard of care in autologous transplants. They are being used in allogeneic transplants, though it may lead to a higher likelihood of chronic GVHD.

• Umbilical cord blood. Uncommonly used for HSCT at this time.

Types of transplants

• Autologous transplants. The recipient donates own stem cells prior to ablative therapy

• Allogeneic transplants. HLA-matched stem cells from a relative of the recipient, or an unrelated donor. Cells are administered after their own bone marrow is ablated.

• Nonmyeloablative stem cell transplants. Also called “mixed chimeric” transplants or ‘mini-transplants.” Allogeneic stem cells are infused after a non-myeloablative conditioning regimen, leading to a marrow populated by both donor and host stem cells. The engrafted donor stem cells may be effective alone, or donor leukocytes can be infused to induce a greater graft versus tumor effect.

• Syngeneic transplants. Donor and recipient are identical twins. Higher failure rate due to decreased graft-versus-tumor effect. GvHD is rare and is likely different than classical allogeneic GvHD.

Transplantation process

• Transplant day is day “0.” Patients are day –5 when they are 5 days prior to transplant, and day +60 two months post-transplant.

• Pre-transplant evaluation and donor screening

• Stem cells are harvested from donor (which may be the recipient in case of autologous SCT)

• Recipient marrow is ablated with a “conditioning” regimen (this may be total or partial depending on type of transplant).

– Regimen consists of cytotoxic chemotherapy and/or total body irradiation (TBI). Usual conditioning chemo regimens may include cyclophosphamide, busulfan, melphalan, or other alkylating agents.

• Stem cells engraft (locate to bone marrow and begin to produce cells).

• Engraftment is defined as the achievement of an ANC greater than 0.5. The process is also manifest by increase in red cells and platelets, and may include fever, fluid retention and decreasing potassium and phosphate levels.

• Autologous transplants engraft in approximately 10 days, while allogeneic transplants take 14-21 days. Delays in engraftment may be due to graft rejection, or viral infection (CMV, HHV, EBV)

• Monitor for and treat complications (more below)

• Management of immunosuppression continues throughout the transplantation process, minimizing risk GvHD while maximizing the graft-versus-tumor Monitor for disease recurrence

Acute complications of HSCT (days 0 through +100)

• Engraftment syndrome (associated with allogeneic transplant more often than auto)

– During neutrophil recovery and engraftment, clinical syndrome of fever, erythrodermatous rash >25% of body area, pulmonary edema as well as hepatic dysfunction, renal insufficiency, weight gain

– Occurs within 96 hours of engraftment

– Treated with corticosteroids, often with good response

• Graft versus host disease (GvHD). Acute GvHD is most common in allogeneic transplants, but can complicate autologous and rarely syngeneic transplants. Presence of GvHD may correlate with a beneficial graft versus tumor (GvT) effect. Involves skin, GI tract, and the liver.

– Skin. Usually the first system involved, and the most common. An erythematous maculopapular rash generally involves the neck, ears, shoulders, trunk, the palms and soles. It can become confluent, and in severe forms bullous and desquamating.

– Hepatic. Liver GvHD generally presents with elevated conjugated bilirubin and alk phos due to damage to the bile canaliculi. The differential diagnosis of elevated LFTs after HSCT also includes veno-occlusive disease of the liver (more below), drug toxicity and infection. May need liver biopsy.

– Intestinal. Manifests with diarrhea, and may lead to severe high output diarrhea with grave consequences. Differential diagnosis of diarrhea post HSCT also includes C. difficile colitis and other infections, as well as drug effects. Rectal biopsy may helpful for diagnosis.

– Treatment. Patients receive prophylaxis, generally with cyclosporine and methotrexate. Treatment of acute GvHD begins with steroids as first line (usually methylprednisolone). Second line agents include tacrolimus, antithymocyte globulin, and mycophenolate mofetil.

• Graft rejection. Most commonly seen with HLA mismatched transplants, T-cell depleted transplants, and transplants for aplastic anemia. Manifest by failure to engraft, and has very high mortality.

• Infection. Due to the high infectious risk secondary to the leukopenia that precedes engraftment, HSCT patients are given aggressive antimicrobial prophylaxis. This generally includes a quinolone for bacteria, TMP/SMX for PCP, acyclovir for HSV, fluconazole for Candida sp., and pre-emptive ganciclovir if positive for CMV. Leukocyte production is stimulated with growth factors (G-CSF or GM-CSF). Growth factor therapy is begun 24-72 hours post-transplant and continued until neutrophil recovery is achieved.

• Veno-occlusive disease of the liver (VOD). Begins with injury to hepatic venous endothelium, and is a procoagulant state. Risk factors include pre-existing liver disease, certain types of induction or conditioning chemotherapy, high dose radiation, estrogen therapy, and mismatched transplants.

– VOD manifests as hyperbilirubinemia, jaundice, hepatomegaly, RUQ pain and weight gain secondary to ascites. Patients receive ursodiol or low dose heparin for prophylaxis of VOD.

– Treatment is far more difficult, consisting of supportive care and may include tPA, LMWH, antithrombin-III, or defibrotide.

• Pulmonary disease. Pulmonary infections may occur with bacterial and fungal pathogens, and may include viral pathogens such as CMV, RSV, influenza, parainfluenza, HSV, and adenovirus. Mycobacterial and pneumocystis infections can occur. Other pulmonary complications include diffuse alveolar hemorrhage, ARDS, and idiopathic pneumonia syndrome.

• Cardiac disease. Myocarditis or pericarditis may occur, generally related to conditioning chemotherapy with high dose cyclophosphamide.

• Bleeding. Thrombocytopenia post transplant must be monitored carefully, and transfused generally to keep over 20k. Single donor platelets should be used due to allo-immunization. HLA-matched platelets are also an option for patients with high platelet-reactive antibodies. Bleeding sites may include line sites, mucositis, bowel, and hemorrhagic cystitis, among others.

Chronic complications of HSCT (after day +100)

• Chronic GvHD. Presence of chronic GvHD is the most important factor determining long-term outcome and quality of life following allogeneic HSCT. It occurs in 30 to 50% of allogeneic transplants. It can occur after previous acute GvHD disease or without, though previous GvHD is the strongest risk factor for the chronic form.

– Chronic GvHD leads to immunodeficiency by direct immunosuppressive effects of the GvHD, as well as the immunosuppressive medications used for treatment, and therefore a legion of infections can occur. Manifestations are similar to chronic autoimmune diseases such as SLE, scleroderma, and primary biliary cirrhosis. Primary involved organs in chronic GvHD include skin, GI tract, liver, and lungs.

– Skin. May be diffuse or limited. Diffuse disease involves generalized erythema and desquamation, and may involve to resemble scleroderma or lichen planus.

– GI tract. Marked by dry mucous membranes and painful ulcerations. Esophageal involvement may lead to ulcerations, strictures, and webs. Small and large bowel involvement may lead to chronic diarrhea and malabsorption syndromes.

– Hepatic. May lead to chronic hepatitis and cirrhosis

– Lung. Bronchiolitis obliterans can occur and presents with dyspnea and dry cough. Pulmonary fibrosis secondary to chemotherapy or radiation also must be considered.

– Treatment. Consists primarily of immunosuppression with typical agents such as steroids, cyclosporine, azathioprine, and tacrolimus. Newer agents include thalidomide, mycophenolate mofetil, rituximab, and rapamycin.

• Infection

– Infections due to the immunocompromised state can include bacterial, fungal, viral (especially CMV and RSV), PCP, and mycobacterial pathogens.

• Posttransplant lymphoproliferative disease (PTLD)

– EBV-related and seen primarily in recipients of T-cell depleted allografts. May consist of a polyclonal B-cell proliferation presenting as an infectious mononucleosis-type illness, with or without evidence of early malignant transformation. A second form is a malignant, monoclonal, and primarily extranodal B-cell proliferation.

– Treatment for the benign form consists of reducing immunosuppression, and advanced therapy only if that fails. The malignant form is treated with rituximab with or without chemotherapy and radiation. Prophylactic rituximab is being investigated in patients with EBV reactivation.

• Secondary malignancy.

– Hematologic malignancies, such as AML and MDS, as well as non-hematologic malignancies, are increased in the post HSCT population. The patterns of post transplant malignancy differ by indication for transplant, type of conditioning regimen used, and other factors.

Red blood cells

• 1 unit = 300 mL: 200ml RBC, 100 mL plasma (Hct = 70%); it increases patient’s Hct 3-4% per unit

Indications

• Symptoms of anemia (levels vary), acute blood loss

• Hct < 21. Maintain Hct 21-24 in critical illness (except in acute coronary syndromes)

• Hct < 25 significant underlying cardiovascular disease

• To “prevent ischemia”

– Age < 40, Hct ................
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