Cancer Treatment

Stem cell transplantation for CML

Despite improvement of treatment with Gleevec, allogeneic stem cell transplantation remains the only curative treatment for patients with CML.[1]  This form of treatment is only available for a small minority of patients due to the advanced age of most patients at the time of diagnosis and the lack of a suitable related or unrelated allogeneic stem cell donor. Despite significant progress, allogeneic transplants are associated with significant early mortality and morbidity. Until the advent of Gleevec, “young” patients with an HLA-matched related or unrelated donor were advised to undergo a transplant without a trial of IFNa.  Older patients and patients with high-risk factors for failure of transplantation were advised to have an allogeneic transplant only after failure of IFNa. The definition of who is “young” and who is at “high” risk of transplant failure varies from center to center and is evolving over time. Advising selected patients to have an immediate transplant was based on the observation that the results of transplant were worse for patients transplanted after one or two years than for patients transplanted within one year of diagnosis. Until recently, a major criterion for delay of transplant was a good initial response to IFNa treatment. Now all patients with newly diagnosed CML are receiving initial treatment with Gleevec alone or in combination with other agents before a transplant is considered. However, clinicians should identify a donor early for younger patients without significant co-morbidities since, sooner or later, the disease will progress despite Gleevec and other therapies.NCCN recommends allogeneic tansplant in blast crisis, after obtaining a remission.

Transplantation should be done sooner when there are poor-risk features, such as presentation in blast crisis.Age has consistently been an important factor for outcome of allogeneic stem cell transplantation, but the exact upper age limit for performing an allogeneic transplant in early chronic phase is controversial, with ranges from 40-65 years, depending on the institution performing the procedure. In general, treatment-related deaths increase with age in most centers. In one clinical study, no patients under age 20 died. Patients 30-40, 40-50 and 50-60 years were 1.24, 2.30 and 2.54 times more likely to die of the procedure, respectively.  Patients over age 40 had a significant increase in the risk of dying of the transplant compared to younger individuals. Thus, patients under the age of 40 had a 5-year survival of 85%, compared to 65-70% for patients over 40 years of age.

Delay of transplant can also affect outcomes of patients transplanted in chronic phase. In one study, patients transplanted from HLA-matched unrelated donors while in chronic phase within one year of diagnosis had a 5-year survival of 85% while those transplanted between 1 and 2 years from diagnosis had a survival of 78%.  Patients transplanted in chronic phase more than 2 years from diagnosis had a survival 50%, with the excess deaths all being related to complications of the transplant. However, these data were generated in the era of INF alfa treatment and the impact of Gleevec on survival from a subsequent transplant is unknown. This will be very important since patients will be coming to transplant after years of Gleevec treatment.Allogeneic stem cell transplantation can cure up to 80-85% of patients with newly diagnosed CML but can be associated with significant morbidity and mortality. There have been attempts to define risk factors associated with failure to assist in decision making concerning the appropriate timing of allogeneic stem cell transplantation for an individual patient with CML.  However, these risk factor analyses may be dated and may not be relevant to patients being treated in the Gleevec era and an era of improving results of allogeneic stem cell transplantation.

Gratwohl A, Hermans J, Goldman JM, et al. Risk assessment for patients with chronic myeloid leukaemia before allogeneic blood or marrow transplantation. Lancet . 1998;352:1087-1092.

Appelbaum FR, Clift R, Radich J, et al Bone marrow transplantation for chronic myelogenous leukemia. Semin Oncol. 1995 Aug;22(4):405-11

Hansen JA, Gooley TA, Martin PJ, et al. Bone marrow transplants from unrelated donors for patients with chronic myeloid leukemia. N Engl J Med .1998;338(14):962-8.

Radich JP, Gooley T, Bensinger W, et al. HLA-matched telated hematopoietic cell transplantation for chronic-phase CML using a targeted busulfan and cyclophosphamide preparative regimen. Blood.2003;102:31-35.

Crawlely C, Szdlo R, Lalancette M, et al. Outcomes of reduced-intensity transplantation for chronic myeloid leukemia: an analysis of the prognostic factors from the Chronic Leukemia Working Party of the EBMT. Blood . 2005;106:2969-2976.

Stem cell transplantation for CMML.

Adult Type Chronic Myelomonocytic Leukemia is part of the spectrum of myelogenous leukemias that may have findings that simulate typical chronic myelogenous leukemia (CML) such as anemia, high white cell count and enlargement of the spleen but is often also calssified as a type of myelodysplasia. However, the cells do not contain the Ph chromosome, or BCR-ABL oncogene, that characterizes chronic myelogenous leukemia. The age and general health of the patient are factors when determining the intensity of CMML treatment. Cytarabine, either standard or low-dose, etoposide, hydroxyurea, and other approaches used for the low-blast count myelogenous leukemias have been tried with little success. Stem cell transplantation can be considered in younger patients (<50 years) with a matched donor. Median survival in CMML is about 20 months, with a range from about 10 to over 60 months.

The first MUD transplant in CMML was reported in 1986. Mulltiple series and cases were subsequently reproted as well as retrospective reviews but no prospective randomized studies have been done.Various chemotherapy regimens for CMML have been used with only modest success.

Bone marrow or stem cell transplantation appears to be the only current treatment that alters the natural history of CMML. In a review of 118 young MDS patients (median age 24, age range 0.3–53 years) who received allogeneic bone marrow transplants from matched unrelated donors, the actuarial probability of survival at 2 years for the 12 patients with CMML was 10%. Transplant-related mortality was influenced by the age of the patient (i.e., <18 years, 40%; 18–35 years, 61%; >35 years, 81%). This study included patients who received transplants as early as 1986, which may have influenced the patient survival data.[18][Level of evidence: 3iiiA] In a recent review of 50 allogeneic transplantations for CMML (i.e., median age 44, age range 19–61 years) from related (n = 43) or unrelated (n = 7) donors, the 5-year-estimated overall survival was 21%. The 5-year estimated probability of relapse was 49%. The data showed a trend for a lower relapse probability of acute graft versus host disease grade II through grade IV and for a higher relapse rate in patients with T cell-depleted grafts, suggesting a graft-versus-CMML effect. This latter series represents the largest cohort of patients with adult CMML and allogeneic stem cell transplantation to date.[Level of evidence: 3iiiA

Kröger N, Zabelina T, Guardiola P, Runde V, Sierra J, Van Biezen A, Niederwieser D, Zander AR, De Witte T.Allogeneic stem cell transplantation of adult chronic myelomonocytic leukaemia. A report on behalf of the Chronic Leukaemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT).Br J Haematol. 2002 Jul;118(1):67-73.

http://jco.ascopubs.org/cgi/reprint/15/2/566

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

BCR/ABL monitoring of chronic myelogenous leukemia on Gleevec

There  have been no studies that  demonstrate that followup with BCR/ABL assists with actual clinical management of CML. Chronic myeloid leukemia has become a paradigm for the discovery of target therapeutic approaches in the field of onco-hematology. Recognition of the tyrosine kinase activity of the p210Bcr-Abl oncoprotein led to the development of compounds targeting against BCR-ABL and then controlling the leukemic proliferation. Imatinib mesylate, one of the first tyrosine kinase inhibitors developed, was found effective and safe. According to five-years experience with this drug, it is recommended that the golden standard for initial treatment of newly diagnosis chronic myeloid leukemia patients should be 400 mg Imatinib daily.

It is not clear what the best monitoring stategy of imatinib might be. Some physicians get regular bcr/abl analysis, others only use it for monitoring when Ph chromosome is undetectable. As noted, there is no clear consensus on how to use this test. NCCN does recommedn BCR/ABL every three months.

Gluckman, J. Reiffers, et al.
Imatinib mesylate discontinuation in patients with chronic myelogenous leukemia in complete molecular remission for more than 2 years
Blood, January 1, 2007; 109(1): 58 - 60.

J. V. Melo, T. P. Hughes, and J. F. Apperley
Chronic Myeloid Leukemia
Hematology, January 1, 2003; 2003(1): 132 - 152.

Hematology Disease Site Group. Walker I, Makarski J, Stevens A, Meyer RM. Treatment of chronic myeloid leukemia with imatinib. Toronto (ON): Cancer Care Ontario (CCO); 2004 Jul 16. 27 p. (Practice guideline report; no. 6-15). [39 references]

http://www.cdhb.govt.nz/chlabs/miscdocuments/CML_Monitoring_Guidelines_Jul%202007.pdf

Donor Lymphocyte Infusions (DLI) for CLL

Lay Summary: DLI is well studied in chronic myelogenous leukemia but less so in other hematological conditions.

DLI induces complete remissions in the majority of patients with chronic myeloid leukemia (CML) in early-stage relapse and in less than 30% of patients with relapsed acute leukemia, myelodysplasia, and multiple myeloma. DLI-induced remissions of chronic phase CML are durable, but as many as half of patients with other diseases ultimately relapse. Complications of DLI include acute and chronic graft-vs-host disease (GVHD) and aplasia, which induce profound immunosuppression and susceptibility to opportunistic infections. There is a strong correlation of GVHD and disease response.
Other hematologic malignancies do not respond to DLI as well as early-stage CM. In general, less than 30% of patients with relapsed acute leukemia,myelodysplasia, and multiple myeloma achieve complete responses to DLI. As many close to half or more of patients who do achieve a complete response may be expected to relapse after DLI. 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.

Chronic lymphocytic leukemia (CLL) also appears to be responsive to allogeneic donor T cells.However, clinical expereince is limited.  Some patient have obtained a remission following DLI as treatment of persistent disease following alloBMT. Other CLL patients have obtained complete remissions, including molecular complete remissions, following discontinuation of posttransplant immunosuppression. However, there is not much literature credibly supporting routine use of DLI for CLL.

JAK2 for diagnosis

Lay Summary: JAK2 testing can now be performed for a diagnosis of a myeloproliferative disorder.  This is now an acceptable approach to diagnosing myeloproliferative disorders.

In early 2005, several groups of investigators reported a somatic acquired point mutation in the JAK2 (Janus kinase 2) protein in the blood and bone marrow of patients with BCR/ABL-negative chronic myeloproliferative disorders. JAK2 is a tyrosine kinase which plays an important role in normal hematopoietic growth factor signaling, and the mutation results in activation of the kinase and deregulated intracellular signaling with cell proliferation that is independent of normal growth factor control.

Using sensitive assays, the JAK2 mutation can be detected in approximately 90-95% of cases of polycythemia vera, 50-70% of patients with essential thrombocythemia, and 40-50% of cases of idiopathic myelofibrosis. The mutation has also been described in rare cases of myelodysplastic syndromes, acute myeloid leukemia, systemic mastocytosis and hypereosinophilic syndrome. It is specific for diagnosis of a clonal myeloid lineage proliferative disorder. The mutation has not been described in BCR/ABL-positive chronic myeloid leukemia, any acute or chronic lymphoid disorders, any healthy persons, or any patient with secondary polycythemia or a reactive blood count elevation. The JAK2 test promises to be very useful in distinguishing between clonal myeloproliferative disorders and reactive cellular proliferations.

Mary F. McMullin, John T. Reilly, Peter Campbell, David Bareford, Anthony R. Green, Claire N. Harrison, Eibhlin Conneally, on behalf of the National Cancer Research Institute, Myeloproliferative Disorder Subgroup, Kate Ryan, on behalf of the British Committee for Standards in Haematology (2007)  Amendment to the guideline for diagnosis and investigation of polycythaemia/erythrocytosis
British Journal of Haematology 138 (6), 821–822.

James, C., Ugo, V., Le Couedic, J.P., Staerk, J., Delhommeau, F., Lacout, C., Garcon, L., Raslova, H., Berger, R., Bennaceur-Griscelli, A., Villeval, J.L., Constantinescu, S.N., Casadevall, N. & Vainchenker, W. (2005) A unique clonal JAK2 mutation leading to constitutive signaling causes polycythaemia vera. Nature, 434, 1144–1148.

McMullin, M.F., Bareford, D., Campbell, P., Green, A.R., Harrison, C., Hunt, B., Oscier, D., Polkey, M.I., Reilly, J.T., Rosenthal, E., Ryan, K., Pearson, T.C. & Wilkins, B., General Haematology Task Force of the British Committee for Standards in Haematology. (2005) Guidelines for the diagnosis, investigation and management of polycythaemia/erythrocytosis. British Journal of Haematology, 130, 174–195.

Umbilical cord stem cells

Lay summary: Cord stem cells have been shown to be equivalent to other allogeneic cells for transplantation in leukemia but not yet for other diagnoses.

Cord blood transplatation ifs a fairly recent but rapidly becoming established technique for transplnatation in leukemia. The first unrelated cord blood transplantations were performed in children. The first 25 unrelated cord blood transplantations were reported in 1996. Since then a number of reports appeared. This work has been followed by several studies, showing similar results in children. The New York Blood Center reported on 562 cases, 82% children, who underwent transplantation in a variety of centers with differing conditioning regimens and graft-versus-host disease prophylaxis. However, there have been retrospective matched pair analyses. Two studies in the New England Journal of Medicine reinforce the role of cord-blood transplantation in the treatment of leukemia in adults. Although this treatment is not recommended over HLA-matched donors from unrelated donor sources, it is a viable alternative that can be effective. (N Engl J Med. 2004;351:2255-2265, 2276, 2328). Although guidelines ahve not yet listed this alternative, more recent review articles and an editorial state that it is an equivalently effective approach, even in adults. Both reports reinforce the role of cord-blood transplantation in the treatment of adults with leukemia. It is realistic to anticipate that the current results for cord-blood transplantation in adults with hematologic cancers will contribute to more extended use in the coming years.

J. Aschan Allogeneic haematopoietic stem cell transplantation: current status and future outlook Br. Med. Bull., October 5, 2006; (2006)

Karen K. Ballen New trends in umbilical cord blood transplantation
Blood, 15 May 2005, Vol. 105, No. 10, pp. 3786-3792

Vikram Mathews, MD and John F. DiPersio, MD, PhD Stem Cell Transplantation in Acute Myelogenous Leukemia in First Remission: What Are the Options? Current Hematology Reports 2004,

Interferon for Myeloproliferative disorders

The myeloproliferative disorders consist of polycythemia vera, chronic myelogenous leukemia, agnogenic myeloid metaplasia, and essential thrombocythemia. All these disorders are thought to result from a hematopoietic stem cell lesion.

Interferon alfa is effective in suppressing bone marrow function in chronic myeloproliferative disorders, but this treatment requires multiple weekly injections. Pegylated interferon, on the other hand, can be given weekly. Several groups reported on the results of phase 2 trials of pegylated interferon alfa 2b in essential thrombocytosis and polycythemia vera with generally concordant results.Satisfactory platelet count reduction was achieved with 3 to 6 months of therapy in approximately 70% of patients, but the drug had to be discontinued in 15% to 52% of them because of side effects. In the one study in which marrow histology was examined, progression of myelofibrosis was not inhibited by pegylated interferon. The number of studies and quality fo evidence mmets Caremark criteria for apporval. The therapy is not investigational and it is medically necessary.

Gugliotta L, Bulgarelli S, Tienghi A, et al. Bone marrow biopsy and aspirate evaluation in 90 patients with essential thrombocythemia treated with peg interferon alpha-2b. Preliminary results. Blood. 2004;104:11. Abstract 1523.

Samuelsson J, Hasselbalch H, Bruserud O, et al. A phase II trial of pegylated interferon alpha-2b in polycythemia vera and essential thrombocythemia: clinical responses, effects on PRV-1 expression and impact on quality of life. Blood. 2004;104:11. Abstract 1518.

Langer C, Lengfelder E, Thiele J, et al. Treatment with pegylated interferon alpha (Pegintron) for high-risk essential thrombocythemia: results of a phase II study. Blood. 2004;104:11. Abstract 1522.

Verstovsek S, Lawhorn K, Giles F, et al. PEG-intron for myeloproliferative diseases: an update on ongoing phase II study. Blood. 2004;104:11. Abstract 1517.