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.

Vancyclovir prophylaxis

Cytomegalovirus (CMV) infection after solid organ transplantation is one of the most common viral infections, causing significant morbidity and mortality if not treated promptly. Ganciclovir has proven to be effective for the prophylaxis and treatment of CMV. However, oral absorption of ganciclovir is poor. Recently, oral administration of valganciclovir hydrochloride (Valcyte) has been observed to display 10-fold better absorption than oral ganciclovir. Valganciclovir has increasingly been used as prophylaxis against CMV after solid organ transplantation and for severely immunospuressive cehmo regimens.In kidney recipients, oral valganciclovir for 100 days has been shown to be as clinically effective as oral ganciclovir for CMV prevention. In heart recipients, valganciclovir is also presumed to be effective, but data are more limited. Alemtuzumab is an immunosuppressive antibody that depletes normal T cells and B cells. Prophylaxis for herpes virus and Pneumocystis carinii is standard with this agent. Approximately 20% to 25% of patients will experience cytomegalovirus (CMV) reactivation.A very recent randomized trial found CMV prophylaxis to be effective and beneficial in these patients.

Cincinnati Children's Hospital Medical Center. Evidence-based care guideline for cytomegalovirus prophylaxis following solid organ transplants. Cincinnati (OH): Cincinnati Children's Hospital Medical Center; 2007 Jul 6. 15 p. [68 references] Susan O'Brien, Farhad Ravandi, Todd Riehl, William Wierda, Xuelin Huang, Jeffrey Tarrand, Brandi O'Neal, Hagop Kantarjian, and Michael Keating Valganciclovir prevents cytomegalovirus reactivation in patients receiving alemtuzumab-based therapy Blood 111: 1816-1819; prepublished online as DOI 10.1182/blood-2007-03-080010

ATG for graft versus host disease

Severe acute graft-versus-host disease (GVHD) is one of the major complications after haematopoietic stem-cell transplantation (HSCT). Treatment of severe GVHD is difficult and the condition is often fatal. One proposed method of improving the therapy is to include anti-thymocyte globulin (ATG). ATG is being actively studied for prophylaxis of GVHD after allogeneic transplantation, f. e., the phase II study Sirolimus, Tacrolimus, and Antithymocyte Globulin in Preventing Graft-Versus-Host Disease in Patients Undergoing a Donor Stem Cell Transplant For Hematological, NCT00589563.

However, it appears to not be very effective to treat already established disease. ATG treatment can produce objective responses in patients with aGVHD, but these responses do not result in long-term survival. A recent review consluded: "Given the poor survival rates of patients treated with ATG for steroid-refractory GVHD, treatment with ATG as standard therapy should be reconsidered. Patients with steroid-refractory GVHD should be enrolled in clinical study until there are data to support a standard salvage therapy."

Neumeister P, Zinke W, Sill H, Linkesch W: Treatment of severe acute graft-versus-host disease with anti-thymocyte globulin Clinical transplantation   ISSN 0902-0063 
2001, vol. 15, no3, pp. 147-153 (48 ref.)

S . Arai Poor outcome in steroid-refractory graft-versus-host disease with antithymocyte globulin treatment .  Biology of Blood and Marrow Transplantation , Volume 8 , Issue 3 , Pages 155 - 160, 2002

Rituxan for graft vesus host disease

Chronic GVHD is a major complication of allogeneic stem cell transplantation involving the skin, musculoskeletal system and liver. Chronic GVHD is mediated primarily by T-cells. However, recently there has been emerging evidence that B-cells are also involved. The support for this concept comes from the detection of antibodies to minor HLA antigens. Several pahse II clinical trials evaluated Rituxan for the treatment of chronic GVHD based on the hypothesis that antibody suppression would be beneficial. In aggreagte they show effectiveness. The status of experimental caanot be assigned to this treatmetn because phase III trials are no possible due to the low numbers of patients avaialble for such studies. There is no expert consensus on performing such studies.

http://bloodjournal.hematologylibrary.org/cgi/reprint/2006-01-0233v1.pdf

R . Kamble , M . Oholendt , G . CarrumRituximab Responsive Refractory Acute Graft-versus-Host Disease .  Biology of Blood and Marrow Transplantation , Volume 12 , Issue 11 , Pages 1201 - 1202 2006

Stefan Deneberg etal, Relapse of preB-ALL after rituximab treatment for chronic graft versus host disease. Implications for its use?
Journal Medical Oncology Issue Volume 24, Number 3 / September, 2007

Donor lymphocyte infusion

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. Whetehr a second DLI adds something to GVHD is not known.

While DLI-induced remissions are achieved in only a small number of AML patients, many of these remissions may be durable. Of 10 patients in the North American registry who had achieved a complete remission (CR) from DLI, only two subsequently relapsed at 1–3 years. At a median follow-up of 1 year, five patients were alive and in CR. The two that relapsed died of disease and three other patients had died of treatment-related causes.

The effects of DLI appear to be similar in patients receiving unrelated donor transplants, although only small numbers of recipients of unrelated DLI (UDLI) have been reported. In collaboration with the National Marrow Donor Program, we retrospectively identified 23 AML patients who received UDLI for relapsed AML.5 The median follow-up was 10 weeks (range 4–102 weeks). Of the patients evaluable for response to DLI alone, 42% achieved a CR. However, only 4/23 of all patients (17%) had a durable CR. From this study and others, it is clear that the most significant predictor of survival and disease-free survival (DFS) was the time from transplant to relapse. Of interest, there was no dose–response effect identified in the unrelated donor setting though the majority of patients received more than 1  107 mononuclear cells/kg. This might argue agains a second DLI.

Unfortunately, not only response to DLI in AML is disappointing, but also the toxicity is significant. Up to 30% of patients will develop grade III–IV acute GVHD, and treatment-related mortality rates are estimated to be up to 20%.

Porter D, Collins R, Hardy C, Kernan N, Drobyski W, Giralt S et al. Treatment of relapsed leukemia after unrelated donor marrow transplantation with unrelated donor leukocyte infusions. Blood 2000; 95: 1214–1221.

Leis J, Porter D. Unrelated donor leukocyte infusions to treat relapse after unrelated donor bone marrow transplantation. Leukemia Lymphoma 2002; 43: 9–17.

Levine J, Braun T, Penza S, Beatty P, Cornetta K, Martino R et al. Prospective trial of chemotherapy and donor leukocyte infusions for relapse of advanced myeloid malignancies after allogeneic stem cell transplantation. J Clin Oncol 2001; 20: 405–412.

Christoph Schmid, Myriam Labopin, Arnon Nagler, Martin Bornhäuser, Jürgen Finke, Athanasios Fassas, Liisa Volin, Günham Gürman, Johan Maertens, Pierre Bordigoni, Ernst Holler, Gerhard Ehninger, Emmanuelle Polge, Norbert-Claude Gorin, Hans-Jochem Kolb, Vanderson Rocha Donor Lymphocyte Infusion in the Treatment of First Hematological Relapse After Allogeneic Stem-Cell Transplantation in Adults With Acute Myeloid Leukemia: A Retrospective Risk Factors Analysis and Comparison With Other Strategies by the EBMT Acute Leukemia Working Party Journal of Clinical Oncology, Vol 25, No 31 (November 1), 2007: pp. 4938-4945

Donor Lymphocyte Infusion after Allogeneic Stem Cell Transplantation
ASCO Educational Book, January 1, 2008; 2008(1): 334 - 337.

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

Autologous stem cell transplant for follicular lymphoma

Lay Summary:

The role of AuSCT is not entirely clear in follicular lymphoma.

There are now 3 conflicitng studies of autologous transplant for follicular lymphoma.

Despite nearly identical eligibility criteria and the use of an anthracycline-based induction treatment in all studies, the results are quite different. The previous studies found a significant advantage to autologous stem cell transplantation (ASCT). The German Lymphoma Study Group (GLSG) reported that patients randomized to transplantation had a 64.7% progression-free survival (PFS) rate at 5 years versus 33% with conventional chemotherapy. The Groupe Ouest-Est d'Etude des Leucémies aigues et autres Maladies du Sang (GOELAMS) group reported 60% PFS for those randomized to autologous transplantation versus 48% with conventional chemotherapy. By contrast, the Groupe d'Etude des Lymphomes de l'Adulte (

GELA

) study does not show a significant PFS advantage for autologous transplantation.

The overall role of ASCT in follicular lymphoma continues to be debated. It is an excellent treatment option for the management of younger patients with recurrent disease. In advanced newly diagnosed lymphoma, a survival advantage has yet to be shown; with more prolonged follow-up it may still emerge in the GLSG study. An increased risk for therapy-related acute myeloid leukemia (t-AML) was observed in the GLSG and GOELAMS studies, but this risk may be minimized by modulation of induction and mobilization therapy preceding transplantation. Despite spectacular advances since the introduction of rituximab, many patients with advanced disease and a high Follicular Lymphoma International Prognostic Index (FLIPI) score have disease recurrences. For such patients, the continued study of autologous transplantation, possibly in combination with rituximab for in vivo purging, remains an important area of investigation.

In conclusion, there is no consensus regarding autologous stem ell transplantation for follicular lymphoma. Since some experts lukewarmy advocate it, it should not be considered "not medically necessary', even if it is arguably still investigational.

Koen van Besien Autologous transplantation for follicular lymphoma? Not too soon! Blood, 15 October 2006, Vol. 108, No. 8, pp. 2496-2497.

NCCN.ORG

Stem Cell Transplant for relapsed acute myelogenous leukemia

Refractory and relapsed disease occurs in most acute myelogenous leukemia patients. Salvage chemotherapy offers a 30–70% chance of a second complete remission. Unfortunately, this second remission is usually short lived and salvage chemotherapy is rarely curative. Allogeneic bone marrow transplant, either human leukocyte antigen (HLA)-sibling matched or matched unrelated donor, is the only treatment to offer long-term disease-free survival and possible cure.  Allogeneic transplantation is standard of care after AML relapse.

Estey EH. Therapeutic options for acute myelogenous leukemia.Cancer. 2001 Sep 1;92(5):1059-73.

nccn.org, AML

Socie G. Current issues in allogeneic stem cell transplantation. Hematology. Sep-Oct 2005;10 Suppl 1:63.

Bloodless stem cell transplants

With an estimated 6000000 Jehovah's witnesses worldwide, haematologists may encounter patients who decline blood transfusions as a matter of personal belief.The risks of high-dose chemotherapy include life threatening bleeding from thrombocytopenia and profound anemia. Autologous stem cell transplantation is usually associated with the transfusion of 5 to 20 units of red blood cell or platelets, with the potential side-effects of infectious disease transmission, transfusion reactions, and iron overload. Inabilty ot ransfuse can be accommodates by increasing sue o erythropoietin (although this was shown in one study not to change outcomes), minimizing blood collection and blood sparing techniques.

In recent years, several facilites, such as University of Pennsylkvanis,  have extended their bloodles surgery programs into the area of transplantation. However, this remains supported by case reports abd series only. It might be expected that only successful cases are published since a publication bias applies in this situation. It is also likely that some conditions are less suitable to this approach and this, as well as apropriate patietn selection,  must be explored in clinical trials.

K K Ballen et al,  Case Report  Successful autologous bone marrow transplant without the use of blood product support July 2000, Volume 26, Number 2, Pages 227-229

Estrin JT, Ford PA, Henry DH et al. Erythropoietin permits high-dose chemotherapy with peripheral blood stem-cell transplant for a Jehovah's Witness. Am J Hematol 1997; 55: 51-52

Bone Marrow Transplant. 2008 Feb 4 [Epub ahead of print] Links
SCT in Jehovah's Witnesses: the bloodless transplant.Sloan JM, Ballen K..