Cancer Treatment

Revlimid for myelofibrosis

There are now 2 similarly designed but separate phase 2 studies involving single-agent lenalidomide (CC-5013, Revlimid) in a total of 68 patients with symptomatic myelofibrosis with myeloid metaplasia (MMM). Protocol treatment consisted of oral lenalidomide at 10 mg/d (5 mg/d if baseline platelet count < 100 x 109/L) for 3 to 4 months with a plan to continue treatment for either 3 or 24 additional months, in case of response. Overall response rates were 22% for anemia, 33% for splenomegaly, and 50% for thrombocytopenia. Response in anemia was deemed impressive in 8 patients whose hemoglobin level normalized from a baseline of either transfusion dependency or hemoglobin level lower than 100 g/L. The authors concluded that lenalidomide engenders an intriguing treatment activity in a subset of patients with MMM that includes an unprecedented effect on peripheral blood and bone marrow abnormalities.

Ayalew Tefferi, Jorge Cortes, Srdan Verstovsek, Ruben A. Mesa, Deborah Thomas, Terra L. Lasho, William J. Hogan, Mark R. Litzow, Jacob B. Allred, Dan Jones, Catriona Byrne, Jerome B. Zeldis, Rhett P. Ketterling, Rebecca F. McClure, Francis Giles, and Hagop M. Kantarjian
Lenalidomide therapy in myelofibrosis with myeloid metaplasia
Blood 108: 1158-1164;

Tefferi, Ayalew
Pathogenesis of Myelofibrosis With Myeloid Metaplasia
J Clin Oncol 2005 23: 8520-8530
 

Androgens for anemia

Hypogonadism and anemia are common comorbid conditions in cancer patients. Testosterone replacement may improve such clinical parameters as anemia, sarcopenia, and low libido. Additionally, by increasing hemoglobin levels, testosterone replacement may allow for a dose reduction in recombinant human erythropoietin (rHuEPO), thereby reducing cost. Testosterone is among the oldest drugs in medicine. It has a long efficacy and safety record for its prime role of androgen replacement therapy in men with androgen deficiency.

Testosterone and synthetic analogue androgens have also been used in pharmacological androgen therapy (PAT) to produce androgenic effects on marrow, muscle or bone. Much of this data is now quite old; there are alos many papers on the sue of androgens to treat anemai of hemodulaysis or renal failure.  Although PAT is increasingly being superseded by newer, more expensive drugs, androgens remain cost-effective in many older applications.With the availability of eruthropietin, testosterone as an anemia treatment has become much less popular but has sometimes been combined with erytrithropoietin as an adjunct.

Androgens for anemia of marrow failure states is an old but well supported treatment that should be considered well supported by the medical literature.

Gascon A, Belvis JJ, Berisa F, et al. Nandrolone decanoate is a good alternative for the treatment of anemia in elderly male patients on hemodialysis. Geriatr Nephrol Urol 1999; 9: 67-72

Ballal S, Domoto D, Polack D, et al: Androgens potentiate the effects of erythropoietin in the treatment of anemia of end-stage renal disease. Am J Kidney Dis 17:29–33, 1991

http://bloodjournal.hematologylibrary.org/cgi/reprint/53/3/504.pdf

Harry W. Daniell Androgen Augmentation of Epoetin Journal of Clinical Oncology, Vol 21, Issue 11 (June), 2003: 2224

Thrombophilias in pregnancy

The thrombophilias are a group of disorders that promote blood clotting. Most women with a thrombophilia have healthy pregnancies. However, pregnant women with a thrombophilia may be more likely than other pregnant women to develop a Venous thrombosis or certain pregnancy complications. Even pregnant women without a thrombophilia may be more likely than non-pregnant women to develop a VTE. This is due to normal pregnancy-related changes in blood clotting that limit blood loss during labor and delivery. However, studies suggest that up to 80 percent of pregnant women who develop a pulmonary embolus or other VTE have an underlying thrombophilia. Pulmonary embolus is the leading cause of maternal death in the United States.

The thrombophilias also may contribute to pregnancy complications including:Fetal loss. This may occur late in the first trimester (miscarriage) or in the second or third trimesters (stillbirth). and Placental abruption. In this condition, the placenta peels away from the uterine wall, partially or completely, before delivery. .Some pregnant women with a thrombophilia are treated with low moecular weight heparins, such as Lovenox. However, not all women with a thrombophilia need treatment during pregnancy. A woman and her health care provider should discuss her individual risks of blood clots and pregnancy complications and the severity of her thrombophilia before deciding whether or not she needs treatment.

In general, treatment is not recommended for most pregnant women with one of the less severe thrombophilias (such as factor V Leiden or prothrombin mutations) who have no personal or family history of blood clots or pregnancy complications. The risk of VTE is less than 0.5 percent (1 in 200) in pregnant women with factor V Leiden with no personal or strong family history of VTE.

While MTHFR heterozygosity itself does not increse risk of thrombosis or fetal compications, when combined with the prothrombin mutation, the risk incrases exponentially.

1. Lockwood, C.J. and Bauer, K.A. Inherited Thrombophilias in Pregnancy. UpToDate, April, 13, 2006.
2. Lockwood, C.J. Preventing VTE: Part 3—The Pregnant Patient. Contemporary Ob/Gyn, May 2005, pages 11-12.
3. James, A.H., et al. Thrombosis During Pregnancy and the Postpartum Period. American Journal of Obstetrics and Gynecology, volume 193, number 1, July 2005, pages 216-219.
4. American College of Obstetricians and Gynecologists (ACOG). Thromboembolism in Pregnancy. ACOG Practice Bulletin, number 19, August 2000.
5. American College of Obstetricians and Gynecologists (ACOG). Antiphospholipid Syndrome. ACOG Practice Bulletin, number 68, November 2005.

Oral B12: the best kep secret in medicine

1. Because most clinicians are generally unaware that oral vitamin B₁₂ therapy is effective the traditional treatment for B₁₂ deficiency has been intramuscular injections. However, since as early as 1968, oral vitamin B₁₂ has been shown to have an efficacy equal to that of injections in the treatment of pernicious anemia and other B₁₂ deficiency. Although the majority of dietary vitamin B₁₂ is absorbed in the terminal ileum through a complex with intrinsic factor, evidence for the previously mentioned alternate transport system is mounting.

   In one study, 38 patients with vitamin B₁₂ deficiency were randomized to receive oral or parenteral therapy. Patients in the parenteral therapy group received 1,000 mcg of vitamin B₁₂ intramuscularly on days 1, 3, 7, 10, 14, 21, 30, 60, and 90, while those in the oral treatment group received 2,000 mcg daily for 120 days. At the end of 120 days, patients who received oral therapy had significantly higher serum vitamin B₁₂ levels and lower methylmalonic acid levels than those in the parenteral therapy group. The actual transport mechanism used in this pathway remains unproved, but vitamin B₁₂ is thought to be absorbed "en masse" in high doses. Surprisingly, one study showed that even in patients who had undergone gastrectomy, vitamin B₁₂ deficiency could be easily reversed with oral supplementation.

   Intramuscular injections, although safe and inexpensive, have several drawbacks. Injections are painful, medical personnel giving the injections are placed at risk of needlestick injuries, and administration of intramuscular injections often adds to the cost of therapy. Treatment schedules for intramuscular administration vary widely but usually consist of initial loading doses followed by monthly maintenance injections. One regimen consists of daily injections of 1,000 mcg for one to two weeks, then a maintenance dose of 1,000 mcg every one to three months.

   Although the daily requirement of vitamin B₁₂ is approximately 2 mcg, the initial oral replacement dosage consists of a single daily dose of 1,000 to 2,000 mcg. This high dose is required because of the variable absorption of oral vitamin B₁₂ in doses of 500 mcg or less.¹⁹ This regimen has been shown to be safe, cost-effective, and well tolerated by patients.

1. Kuzminski AM, Del Giacco EJ, Allen RH, Stabler SP, Lindenbaum J. Effective treatment of cobalamin deficiency with oral cobalamin. Blood 1998;92: 1191-8.
2. Lederle FA. Oral cobalamin for pernicious anemia. Medicine's best kept secret? JAMA 1991;265:94-5.
3. Adachi S, Kawamoto T, Otsuka M, Fukao K. Enteral vitamin B₁₂ supplements reverse postgastrectomy B₁₂ deficiency. Ann Surg 2000;232:199-201.
4. Lederle FA. Oral cobalamin for pernicious anemia: back from the verge of extinction. J Am Geriatr Soc 1998;46:1125-7.

Donor lymphocyte infusion to treat chimerism

The donor cell reinfusion in this case is not being used to provide new graft versus leukemia effect but to destroy remaining normal patient cells and to provide engraftment. It ahs been observed that chimerism is risk factor for relapse of the leukemia. The status of DLI to treat disase is still unsettled and the use of DLI to decrease chimerism is even less established. There would have been no objection to a reinfusion of stem cells to re-engraft which I would see as a continuation of the previously approved stem cell transplant. However, using DLI in this fashion is experimental since the contention that it does os is supported by case reports and series only

Because of the large number of acute leukemia patients who relapse after alloBMT, there has been a substantial experience in the treatment of these patients with DLI. Using median doses of >/=108 T cells/kg, DLI alone induces complete remissions in 8% of patients with ALL and 22% of patients with acute myeloid leukemia (AML). When patients who receive chemotherapy prior to DLI are included, complete response rates are significantly higher, ranging from 33% to 37%. However, follow- up of ALL patients reveals few, if any, long-term survivors, although 1 has been reported. Relapse occurs in approximately one quarter to one half of patients with AML in remission after DLI, leaving a long-term survival rate of approximately 10% to 15%.

DLI has been researched as a treatment for a variety of hematologic malignancies, including most prominently chronic myeloid leukemia, but also acute myeloid leukemia, acute lymphocytic leukemia, multiple myeloma, myelodysplastic syndromes, chronic lymphocytic leukemia, Hodgkin’s disease, and non-Hodgkin’s lymphoma. Studies are limited due to small numbers but they have provided evidence that DLI can establish a graft-versus-leukemia/lymphoma effect.

Fewer patients with relapsed myelodysplasia have been treated with DLI. However, because myelodysplasia progresses more slowly than AML, the rate of complete remissions may be higher. The natural history of myelodysplasia patients who enter into a remission following DLI has not been described.

It is not clear whether administration of induction chemotherapy at the time of relapse improves long-term survival following DLI. It is usually thought that it does but without a strong conifrmation in the literature. A randomized trial with analysis performed on an intent-to-treat basis is needed to answer this question.

Litzow, Mark R Progress and strategies for patients with relapsed and refractory acute myeloid leukemia. Current Opinion in Hematology. 14(2):130-137, March 2007.

Luznik L, Fuchs EJ. Donor lymphocyte infusions to treat hematologic malignancies in relapse after allogeneic blood or marrow transplantation.Cancer Control. 2002 Mar-Apr;9(2):123-37.

Ishikawa J, Maeda T, Kashiwagi H, et al. Successful second allogeneic peripheral blood stem cell transplantation and donor leukocyte infusion in patients with relapsed acute leukemia using the same donor as for the initial allogeneic bone marrow transplantation. Bone Marrow Transplantation. 2003; 31:1057-1059.

Levine JE, Braun T, Penza SL, et al. Prospective trial of chemotherapy and donor leukocyte infusions for relapse of advanced myeloid malignancies after allogeneic stem cell transplantation. J Clin Oncol. 2002; 20(2):405-412.

E . Orsini , E . Alyea , A . Chillemi , R . Schlossman , S . McLaughlin , C . Canning , R . Soiffer , K . Anderson , J . Ritz Conversion to full donor chimerism following donor lymphocyte infusion is associated with disease response in patients with multiple myeloma . 
Biology of Blood and Marrow Transplantation , Volume 6 , Issue 4 , Pages 375 - 386, 2000

Suradej Hongeng et al, Donor Lymphocyte Infusion Can Eliminate Mixed Chimerism in Nonmyeloablative Stem Cell Transplantation for Correction of Hyper-IgM Syndrome Acta Hematologica Vol. 114, No. 3, 2005

Intravenous gamma globulin for pure red cell aplasia

Pure red cell aplasia (PRCA) describes a condition in which RBC precursors in bone marrow are nearly absent, while megakaryocytes and WBC precursors are usually present at normal levels. In 1922, Kaznelson recognized that this condition was a different entity than aplastic anemia. Pure red cell aplasia exists in several forms, and the most common form is an acute self-limited condition. Acquired pure red cell aplasia is often chronic and is associated with underlying disorders such as thymomas and autoimmune diseases.

The acquired chronic form of pure red cell aplasia is associated with thymomas and autoimmune disorders. Damage to erythroid progenitors or precursor cells appears to be immune and T-cell mediated. It is tempting to sue IVIG to regulate immune function so as to affect immunologic function. There is sufficient evidence that this is effective and a recent guideline recommends use of IVIG for red cell aplasia. Specific recommendations for routine use of IVIG were made for 7 conditions including acquired red cell aplasia (others were: acquired hypogammaglobulinemia (secondary to malignancy); fetal-neonatal alloimmune thrombocytopenia; hemolytic disease of the newborn; HIV-associated thrombocytopenia; idiopathic thrombocytopenic purpura; and posttransfusion purpura.)

Most studies that show resposne use "high-dose".  Total dose is administered IV but is graduated with low doses initially to monitor for anaphylaxis and other complications. Therefore, doses mentioned in package insert should be followed. Lower dosages/d but extended over 4 d are indicated in patients with fluid overload.  Adult Dose Not to exceed 2 g/kg IV over 4 d
Zimmer J, Regele D, de la Salle H. Pure red-cell aplasia. N Engl J Med. Jun 24 1999;340(25):2004-5.

D . Anderson , K . Ali , V . Blanchette , M . Brouwers , S . Couban , P . Radmoor , L . Huebsch , H . Hume , A . McLeod , R . Meyer Guidelines on the Use of Intravenous Immune Globulin for Hematologic Conditions .  Transfusion Medicine Reviews , Volume 21 , Pages S9 - S56 2007

Interferon for Erdheim Chester

Erdheim-Chester disease is a rare non-Langerhans histiocytosis, with particular tropism for connective and adipose tissues. The infiltrative process preferentially involves the axial skeleton, pituitary, orbit, retroperitoneum, lung, mediastinum and central nervous system. To date, there is no standard treatment for this rare disorder and about two-thirds of the patients succumb to their disease within three years. IFN might be a valuable first-line therapy for prolonged treatment of ECD. However, the efficacy of IFN varies among patients and according to the sites of disease involvement, and symptoms may fail to respond to treatment, especially in patients with severe multisystemic forms of ECD with central nervous system and cardiovascular involvement. There are only case reports and series to support this treatment modality.

Braiteh F, Boxrud C, Esmaeli B, Kurzrock R.Successful treatment of Erdheim-Chester disease, a non-Langerhans-cell histiocytosis, with interferon-alpha.Blood. 2005 Nov 1;106(9):2992-4. Epub 2005 Jul 14.

Julien Haroche et al, Variability in the efficacy of interferon- in Erdheim-Chester disease by patient and site of involvement: Results in eight patients Arthritis Rheum Volume 54, Issue 10 , Pages 3330 - 3336

Treatment of Babesiosis

Antibiotic and antimalarial therapy should begin immediately after diagnosis in symptomatic patients to reduce the level of babesiosis parasitemia. The standard treatment has been clindamycin and quinine, but this regimen occasionally fails and patients report frequent side effects including tinnitus, decreased hearing, and diarrhea. A drug regimen consisting of atovaquone and azithromycin has been shown to be effective and guidelines recomemnd either one of these two combinations. With the former patients experience much fewer side effects, typically diarrhea and rash. Parasitemia may persist despite treatment with either of the described drug regimens. In areas endemic for Lyme disease, physicians should consider treating for Lyme disease empirically.
Evidence-based guidelines for the management of Lyme disease. Expert Rev Anti Infect Ther 2004;2(1 Suppl):S1-13. [66 references]

Wormser GP, Dattwyler RJ, Shapiro ED, Halperin JJ, Steere AC, Klempner MS, Krause PJ, Bakken JS, Strle F, Stanek G, Bockenstedt L, Fish D, Dumler JS, Nadelman RB. The clinical assessment, treatment, and prevention of lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis 2006 Nov 1;43(9):1089-134.

Neupogen to allow ribavirin and interferon treatment of Hepatitits C

Pegylated interferons have been associated with a greater decrease in absolute neutrophil counts than standard interferons, requiring dose reduction secondary to neutropenia in 18-20% of treated patients. While neutropeniais common, rarely is the neutropenia severeenough to warrant permanent discontinuationof therapy. If the neutrophil count drops below0.75 x 109 / L, the pegylated interferon doseshould be reduced by 50%. If the neutrophilcount falls below 0.50 x 109 / L, therapy shouldbe discontinued. Neutrophil counts usuallyreturn to pretreatment levels within four weeksof stopping therapy. Based upon the concern ofneutropenia, many physicians have advocatedthe use of granulocyte-colony stimulating factor(G-CSF) at a dose of up to 300 ug subcutaneouslyper week. Currently, there are no clinical trials to demonstrate the effectiveness of G-CSF although clinical experience does support its efficacy in certain situations. Guidelines state: "Routine use of growth factors, such as epoetin and granulocyte colony-stimulating factor (G-CSF) was considered but not recommended". At this time there is an absence of data supporting the preemptive use of growth factors in this patient population.

In this case, the use is not routine but in order to enable therapy for hepatitis C.Many patients with chronic hepatitis C (HCV) infection undergoing treatment with pegylated interferon-alpha (PEG-IFN-alpha) and ribavirin develop neutropenia requiring dose reduction or granulocyte colony-stimulating factor (G-CSF) supplement. The VA wrote guidelines supporting its use under some conditions, but leukopenia has to be demonstrated first on interferon/ribavirin and dose reduction is to be pursued before Meupogen is used. In a recent database of patients who completed treatment for chronic HCV infection between 2003 and 2006, patients with absolute neutrophil counts below 1000 cells/microL were initiated on G-CSF (G-CSF group) while a matching group of patients who received anti-HCV treatment without developing neutropenia were used as a control group (non-G-CSF group). Patients on the G-CSF arm were divided into two subgroups based on the timing of G-CSF administration relative to PEG-IFN-alpha administration. Of the 163 patients with HCV infection, 30 patients received G-CSF, most of who were maintained on 300 microg of G-CSF once a week. Administration of G-CSF 2 days before or after each dose of PEG-IFN-alpha did not make a significant difference in the neutrophil counts. In the G-CSF arm, 23 of 30 patients (77%) had undetectable end-of-treatment viral response which was comparable with 27 of 30 in the control group (90%; P = 0.17). There was no statistically significant difference in the sustained viral response between the two groups (61%vs 76%, P = 0.18). In most patients PEG-IFN-alpha induced neutropenia improved with a once-a-week dose of G-CSF with a comparable virological outcome. Timing of G-CSF administration did not make any significant impact on the patient's neutrophil counts but was better tolerated when given 2 days apart from PEG-IFN-alpha.

NY State Gudielines for Hep. C. -  http://www.health.state.ny.us/diseases/communicable/hepatitis/guidelines/appena.htm

Strader DB, Wright T, Thomas DL, Seeff LB. Diagnosis, management, and treatment of hepatitis C. Hepatology 2004 Apr;39(4):1147-71. [213 references]

http://www.pbm.va.gov/criteria/GSCFCriteriaForUseforHepatitisC.pdf

Koirala J, Gandotra SD, Rao S, Sangwan G, Mushtaq A, Htwe TH, Adamski A, Blessman D, Khardori NM. Granulocyte colony-stimulating factor dosing in pegylated interferon alpha-induced neutropenia and its impact on outcome of anti-HCV therapy.
J Viral Hepat. 2007 Nov;14(11):782-7.

Is Waldenstrom's a "cancer"?

Waldenstrom's (WM) should be considered cancer since it is apresentation of a lymphoma. WM is an uncommon lymphoproliferative disorder characterized primarily by bone marrow infiltration and IgM monoclonal gammopathy. It should be considered a distinct clinicopathological entity rather than a clinical syndrome secondary to IgM secretion.  Waldenström macroglobulinemia is a clonal disorder of B lymphocytes. This condition is considered to be lymphoplasmacytic lymphoma as defined by the Revised European American Lymphoma Classification (REAL) and World Health Organization (WHO) classification. The concentration of monoclonal IgM can vary widely in WM and it is not possible to define a concentration that reliably distinguishes WM from monoclonal gammopathy of undetermined significance (MGUS) and other lymphoproliferative disorders. A diagnosis of WM can therefore be made irrespective of IgM concentration if there is evidence on a bone marrow trephine biopsy of bone marrow infiltration by lymphoplasmacytic lymphoma with predominantly an intertrabecular pattern, supported by appropriate immunophenotypic studies.

Owen RG, Treon SP, Al-Katib A, Fonseca R, Greipp PR, McMaster ML, Morra E, Pangalis GA, San Miguel JF, Branagan AR, Dimopoulos MA.
Clinicopathological definition of Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom's Macroglobulinemia.Semin Oncol. 2003 Apr;30(2):110-5.

Dimopoulos MA, Panayiotidis P, Moulopoulos LA, et al: Waldenstrom's macroglobulinemia: clinical features, complications, and management. J Clin Oncol 2000 Jan; 18(1): 214-26

Dimopoulos MA, Galani E, Matsouka C: Waldenstrom's macroglobulinemia. Hematol Oncol Clin North Am 1999 Dec; 13(6): 1351-66