Cancer Treatment Today » Stem Cell Transplantation

Velcade for Graft Versus Host DIsease – pro

M Levin, MD — Wed, 16 Oct 2013 21:01:41 +0000

Koreth found that Velcade was beneficial in GVHD; but his was a phase II trial and other phase II trials are ongoing. He found that i the 45 patients who were treated in the study; 89% of patients were treated with a one-locus and 11% of patients were treated with a two-loci mismatch. With a median follow-up of 3 years, the 180-day cumulative incidence of grade 2 to 4 acute GVHD was 22%, and the 1-year cumulative incidence of chronic GVHD was 29%. The non-relapse mortality rate was only 11%, and the relapse rate was 38%. Results were comparable with patients who received HLA-matched transplants with the unexpected observation that bortezomib therapy enhanced immune reconstitution on the basis of measurements of CD8+ T cells and natural killer cells.
The editorial by Giralt that accompanied Koreth report, pointed out that there are four potential current approaches that all are at the same stage of development and that it may be necessary to perform a randomized phase III trial with a short primary end point to be able to rapidly pick a winner from among these competing approaches, one that could be compared with the current standard in a definitive trial.

Koreth J, Stevenson KE, Kim HT, McDonough SM, Bindra B, Armand P, Ho VT, Cutler C, Blazar BR, Antin JH, Soiffer RJ, Ritz J, Alyea EP 3rd. Bortezomib-based graft-versus-host disease prophylaxis in HLA-mismatched unrelated donor transplantation.J Clin Oncol. 2012 Sep 10;30(26):3202-8.

Teresa Caballero-VelázquezPhase II clinical trial for the evaluation of bortezomib within the reduced intensity conditioning regimen (RIC) and post-allogeneic transplantation for high-risk myeloma patients. Phase II clinical trial for the evaluation of bortezomib within the reduced intensity conditioning regimen (RIC) and post-allogeneic transplantation for high-risk myeloma patients, British Journal of Haematology, Volume 162, Issue 4, pages 474–482, August 2013

Koreth J, Stevenson KE, Kim HT, McDonough SM … Antin JH, Soiffer RJ, Ritz J, Alyea EPBortezomib-Based Graft-Versus-Host Disease Prophylaxis in HLA-Mismatched Unrelated Donor Transplantation. J Clin Oncol. 2012 Aug 6

For Lay version see here

Allogeneic Transplant for ALL – pro

M Levin, MD — Sat, 01 Sep 2012 22:17:44 +0000

Lay Summary: The accepted situations that warrant allogeneic transplants for ALL are discussed.

Most current induction regimens for adult acute lymphoblastic leukemia (ALL) include prednisone, vincristine, and an anthracycline. Some regimens also add other drugs, such as asparaginase or cyclophosphamide. Current multiagent induction regimens result in complete response rates that range from 60% to 90%. However some patients relapse and salvage therapy is inadequate for cure. Poor risk ALL is also considered appropriate for consolidation allogeneic transplantation, but NCCN recommends it only when a donor is available (ALL-6).

The goal of stem cell transplantation is to cure the patient’s cancer by destroying the cancer cells in the bone marrow with high doses of chemotherapy and then replacing them with new, healthy blood-forming stem cells.

The accepted benefits of allogeneic hematopoietic cell transplantation (HCT) are due to both the myeloablative chemoradiotherapy and the immune-mediated reaction of donor lymphocytes directed against residual ALL cells in the recipient (ie, the graft-versus-leukemia reaction). To be effective, the survival benefit should outweigh the greater expense and higher risk of early toxicity and death, and late complications such as graft-versus-host disease (GVHD) and sterility. Allogeneic HCT is commonly used as part of the post-remission therapy of patients with ALL demonstrating high-risk features, such as the presence of the Philadelphia (Ph) chromosome or a Ph-like molecular signature [3]. Results have been best when allogeneic HCT is performed in first CR, but allogeneic HCT can also cure some patients in second CR.Franco J. et al, How I treat relapsed childhood acute lymphoblastic leukemia Blood October 4, 2012 vol. 120 no. 14 2807-2816

L.S Muffly et al, Management of Acute Lymphoblastic Leukemia in Young Adults. Clinical Advances in Hematology & Oncology
February 2018 – Volume 16, Issue 2

Goldstone AH, Richards SM, Lazarus HM, et al. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: Final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood. 2008; 111(4): 1827-1833The goal of stem cell transplantation is to cure the patient’s cancer by destroying the cancer cells in the bone marrow with high doses of chemotherapy and then replacing them with new, healthy blood-forming stem cells.

L.S Muffly et al, Management of Acute Lymphoblastic Leukemia in Young Adults. Clinical Advances in Hematology & Oncology February 2018 – Volume 16, Issue 2

A 2009(Imrie et al) guideline considers allogenec transplantation appropriate for:

Acute Lymphoblastic Leukemia (ALL) (including lymphoblastic lymphoma)

First complete remission:
Allogeneic stem cell transplantation is an option for patients with ALL with poor prognostic features such as Philadelphia chromosome or t(4;11) positivity or delayed time to first complete remission.
Autologous stem cell transplantation is not recommended for patients with ALL in first complete remission.
Beyond first complete remission:
Allogeneic transplantation is the recommended treatment option for eligible patients with ALL who achieve a second remission.

A 2012 review presented retrospective reviewes and reports that suggest that umbilical cord is as effective as a sibling donor for children with ALL treated with stem cell transplantation but there remain no comparative studies.

There is insufficient evidence to support or refute the use of autologous stem cell transplantation beyond first remission for patients with ALL.

Franco J. et al, How I treat relapsed childhood acute lymphoblastic leukemia Blood October 4, 2012 vol. 120 no. 14 2807-2816
Stem cell transplant for acute lymphocytic/lymphoblastic leukemia (adult). Philadelphia (PA): Intracorp; 2005. Various p. [47 references]

Evidence-based Reviews, American Society of Blood and Marrow Transplantation. 2004. Published in Biology of Blood and Marrow Transplantation and available online at: http://www.asbmt.org/policystat/policy.html

Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, Fielding AK, Burnett AK, Chopra R, Wiernik PH, Foroni L, Paietta E, Litzow MR, Marks DI, Durrant J, McMillan A, Franklin IM, Luger S, Ciobanu N, Rowe JM. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993).Blood. 2008 Feb 15;111(4):1827-33. Epub 2007 Nov 29.

S. Giebel, Hematopoietic Stem Cell Transplantation for Adults With Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia in First Remission: A Position Statement of the European Working Group for Adult Acute Lymphoblastic Leukemia (EWALL) and the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant. 2019 Jun;54(6):798-809

L.S Muffly et al, Management of Acute Lymphoblastic Leukemia in Young Adults. Clinical Advances in Hematology & Oncology
February 2018 – Volume 16, Issue 2

Imrie K, Rumble RB, Crump M, Advisory Panel on Bone Marrow and Stem Cell Transplantation, Hematology Disease Site Group. Stem cell transplantation in adults: recommendations. Toronto (ON): Cancer Care Ontario Program in Evidence-based Care; 2009 Jan 30. 78 p. (Recommendation report; no. 1). [66 references]

Ashfaq K, Yusuf BJ, Jilani AZ, Owais SS, Yahaya I, Chen Y-F, Kinsey SE. Stem cell transplantation for high risk acute lymphoblastic leukaemia in paediatric patients in first remission. Cochrane Database of Systematic Reviews 2013, Issue 2. Art. No.: CD010348. DOI: 10.1002/14651858.CD010348 – See more at: http://summaries.cochrane.org/CD010348/stem-cell-transplantation-for-high-risk-acute-lymphoblastic-leukaemia-in-paediatric-patients-in-first-remission#sthash.BjAlEfXA.dpuf

EJohn Moore,et al,Equivalent Survival for Sibling and Unrelated Donor
Allogeneic Stem Cell Transplantation for Acute Myelogenous Leukemia, Biology of Blood and Marrow Transplantation 13:601-607 (2007)

Russell JA, Savoie ML, Balogh A, et al. Allogeneic transplantation for adult acute leukemia in first and second remission with a novel regimen incorporating daily intravenous busulfan, fludarabine, 400 cGy total-body irradiation, and thymoglobulin. Biol Blood Marrow Transplant. 2007; 13(7):814-821.

Schetelig J, Bornhäuser M, Schmid C, et al. Matched unrelated or matched sibling donors result in comparable survival after allogeneic stem-cell transplantation in elderly patients with acute myeloid leukemia: a report from the cooperative German transplant study group. J Clin Oncol. 2008; 26(32):5183-5191.

Kiehl MG, Kraut L, Schwerdtfeger R, et al. Outcome of allogeneic hematopoietic stem-cell transplantation in adult patients with acute lymphoblastic leukemia: No difference in related compared with unrelated transplant in first complete remission. J Clin Oncol. 2004; 22(14):2816-2825.

Revised: 8/22/11

Second Allogeneic Transplant in ALL – pro

M Levin, MD — Mon, 13 Aug 2012 15:15:09 +0000

ALL is the most common cancer diagnosed in children and young adults represents almost 25% of cancers in children younger than 15 years. Complete remission of disease is now typically achieved with pediatric chemotherapy regimens in approximately 95% of children with ALL, with up to 85% long-term survival rates. Young adults are treated as children, but the relapse rate is higher.

Relapsed patients can re-transplanted, receive DLI or go into clinical trials. O’Brien looked at 288 patients who received second salvage therapy for ALL and found that they have poor prognosis. It is tempting to retransplant patients who relapse despite an allogeneic transplant. A second BMT results in long-term event-free survival in only 10–20% of patients with relapsed ALL. Only 7–20% of patients has been reported to reach the stage of a second BMT after relapse according to the performance and remission status after salvage chemotherapy. Moreover, second BMT is associated with extremely high treatment-related mortality, ranging from 40% to 50%.

Thus, the outlook for patients with post-transplant relapse of acute leukemia is extremely poor; currently, no single therapy consistently results in durable remissions. There are no guidelines recommending a second allogeneic transplant and it is hard to see why a stem cell transplant would work better a second time unless something different is done.

Fagioli, F, Zecca, M, Rognoni, C, et al. Allogeneic Hematopoietic Stem Cell Transplantation for Philadelphia-Positive Acute Lymphoblastic Leukemia in Children and Adolescents: A Retrospective Multicenter Study of the Italian Association of Pediatric Hematology and Oncology (AIEOP). Biol Blood Marrow Transplant. 2011 Oct 20.

Gonzalez-Vicent, M, Molina, B, Andion, M, et al. Allogeneic hematopoietic transplantation using haploidentical donor vs. unrelated cord blood donor in pediatric patients: a single-center retrospective study. Eur J Haematol. 2011 Jul;87(1):46-53.

Nemecek, ER, Ellis, K, He, W, et al. Outcome of myeloablative conditioning and unrelated donor hematopoietic cell transplantation for childhood acute lymphoblastic leukemia in third remission. Biol Blood Marrow Transplant. 2011 Dec;17(12):1833-40. PM

Pui, CH, Pei, D, Campana, D, et al. Improved prognosis for older adolescents with acute lymphoblastic leukemia. J Clin Oncol. 2011 Feb 1;29(4):386-91.

Arellano ML, Langston A, Winton E, Flowers CR, Waller EK. Treatment of relapsed acute leukemia after allogeneic transplantation: a single center experience.Biol Blood Marrow Transplant. 2007 Jan;13(1):116-23.

Terwey TH, Massenkeil G, Tamm I, Hemmati PG, Neuburger S, Martus P, Dörken B, Hoelzer D, Arnold RSO Allogeneic SCT in refractory or relapsed adult ALL is effective without prior reinduction chemotherapy.Bone Marrow Transplant. 2008;42(12):791.
B O’Brien S, Thomas D, Ravandi F, Faderl S, Cortes J,orthakur G, Pierce S, Garcia-Manero G, Kantarjian HMSOCancer. Outcome of adults with acute lymphocytic leukemia after second salvage therapy. Cancer 2008;113(11):3186.

NCCN, ALL, ALL-7 2012

Repeat Allogeneic Stem Cell Transplantation for ALL – pro

M Levin, MD — Fri, 03 Aug 2012 14:01:40 +0000

Pui, CH, Pei, D, Campana, D, et al. Improved prognosis for older adolescents with acute lymphoblastic leukemia. J Clin Oncol. 2011 Feb 1;29(4):386-91.

Terwey TH, Massenkeil G, Tamm I, Hemmati PG, Neuburger S, Martus P, Dörken B, Hoelzer D, Arnold RSO Allogeneic SCT in refractory or relapsed adult ALL is effective without prior reinduction chemotherapy.Bone Marrow Transplant. 2008;42(12):791. B O’Brien S, Thomas D, Ravandi F, Faderl S, Cortes J,orthakur G, Pierce S, Garcia-Manero G, Kantarjian HMSOCancer. Outcome of adults with acute lymphocytic leukemia after second salvage therapy. Cancer 2008;113(11):3186.

NCCN, ALL, ALL-7 2012

Read the Layperson version here.

Stem Cell Transplantation in ALL – pro

M Levin, MD — Sat, 30 Jun 2012 12:10:11 +0000

Patients with relapsed acute lymphoblastic leukemia (ALL) have an extremely poor prognosis. Patients with acute lymphoblastic leukemia (ALL) who experience a relapse following chemotherapy and maintenance therapy are unlikely to be cured by further chemotherapy alone. These patients should be considered for reinduction chemotherapy followed by allogeneic bone marrow transplantation. Reinduction regimens include the hyper-CVAD protocol and high-dose Ara-C–based regimens. There is no preferred protocol at this time as investigtion has not yet identified a superior regimen.

Relatively few studies have compared transplantation with chemotherapy in adults with acute lymphoblastic leukemia (ALL) and results are contradictory. It is generally accepted now that with the decrease in transplant mortality stem cell transplantation, especially allogeneic transpalntation is indicated in relapsed ALL.

Patients with Ph1-positive ALL, meaning those preceded by CML, will often be taking imatinib at the time of relapse and thus will have imatinib-resistant disease. Dasatinib, a novel tyrosine kinase inhibitor with efficacy against several different imatinib-resistant BCR/ABL mutants, has been approved for use in Ph1-positive ALL patients who are resistant to or intolerant of imatinib. The approval was based on a series of trials involving patients with chronic myelogenous leuekmia, one of which included small numbers of patients with lymphoid blast crisis or Ph1-positive ALL. In one study, 10 such patients were treated with dasatinib in a dose escalation study. Seven of these patients had a complete hematologic response (<5% marrow blasts with normal peripheral blood counts), three of whom had a complete cytogenetic response. The common toxicities were reversible myelosuppression (89%) and pleural effusions (21%). Virtually all of these patients relapsed within 6 months of the start of treatment with dasatinib. It si thus evident that transpalntation remains appropriate even for these patients.

Pui CH, Evans WE.Treatment of acute lymphoblastic leukemia. Engl J Med. 2006 Jan 12;354(2):166-78.

Samuel ED, Sakamoto KM.. Topics in pediatric leukemia–acute lymphoblastic leukemia.MedGenMed. 2005 Mar 7;7(1):23

Pui, Ching-Hon, Evans, William E.
Treatment of Acute Lymphoblastic Leukemia
N Engl J Med 2006 354: 166-178

http://www.asbmt.org/policystat/policy.htm

Refractory Acute Lymphocytic Leukemia: Role of Stem Cell Transplantation – pro

M Levin, MD — Sat, 30 Jun 2012 11:41:43 +0000

Although acute lymphoblastic leukemia is curable in one third of adult patients, results vary greatly on account of different clinical, immunologic, and cytogenetic/genetic characteristics. These data, along with the kinetics of response to early treatment, help establish the individual risk class with considerable accuracy, and support risk-specific treatments that should warrant optimal results with as little as possible nonrelapse mortality. Modern first-line therapy consists of standard- and high-dose chemotherapy (increasingly inspired to pediatric principles), hematopoietic stem-cell transplantation, and new targeted therapy, all integrated with the analysis of prognostic factors and the study of subclinical residual disease for key therapeutic decisions. These changes are improving long-term outcome, which in ongoing studies is expected close to 50% or greater.

When ALL does not respond, the prognosis is grim. What to do is not known. Clofarabine has been approved for this situation in pediatric ALL and various combination treatmetns are being explored. Clolar® (clofarabine) Injection is indicated for the treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia after at least two prior regimens. CBMT(Canadian BMT Group) suggests that such pateints should be enrolled into clinical trials. It is generallya ccepted, however, that at the very least, a remission be obtained before an allogeneic transplant is attempted.

Relatively few studies have compared transplantation with chemotherapy in adults with acute lymphoblastic leukemia (ALL). The Italian ALL R-87 study suggested that a small number of patients who experience relapse will survive long-term after allogeneic bone marrow transplantation (BMT).

Bassan R, Hoelzer D. Modern therapy of acute lymphoblastic leukemia. J Clin Oncol. 2011;29:532-43.

Advani AS, Gundacker HM, Sala-Torra O, et al. Southwest Oncology Group Study S0530: a phase 2 trial of clofarabine and cytarabine for relapsed or refractory acute lymphocytic leukaemia. Br J Haematol. 2010;151:430-434.

Giona F, Annino L, Rondelli R, Arcese W, Meloni G, Testi AM, et al. Treatment of adults with acute lymphoblastic leukaemia in first bone marrow relapse: results of the ALL R-87 protocol. Br J Haematol. Jun 1997;97(4):896-903. [Medline].

Kantarjian H, Gandhi V, Cortes J, Verstovsek S, Du M, Garcia-Manero G, et al. Phase 2 clinical and pharmacologic study of clofarabine in patients with refractory or relapsed acute leukemia. Blood. Oct 1 2003;102(7):2379-86.

CBMT – http://cancertreatmenttoday.org/wp-content/uploads/2012/06/Stem-Cell-Transplantation-for-Acute-Lymphoblastic-Leukemia1.pdf

nccn. ALL, ALL-7, 2013 and MS-27