Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia: To Transplant or Not to Transplant?

For patients with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL), hematopoietic stem cell transplantation (HSCT) in first remission has historically been considered the standard of care. The introduction of tyrosine kinase inhibitors (TKIs) and newer targeted therapies, however, led to a reevaluation of the role of HSCT in these patients. In this Point | Counterpoint session, Nicholas J. Short, MD, Assistant Professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston, and Jonathan Webster, MD, Assistant Professor of Oncology at The Johns Hopkins University School of Medicine in Baltimore, discussed their differing views of the current position of HSCT in the treatment of Ph+ ALL.

Where, if anywhere, does HSCT fit into the treatment algorithm for Ph+ ALL?

Dr. Webster: One problem we have in considering HSCT in these patients is that we don’t have great randomized studies. Most of the data we do have is biased by which patients were able to get HSCT and which were not. However, there are historical data and two more recent pieces of evidence that push toward thinking about a transplant for most of my patients. The most recent study with HSCT after TKI therapy, by the GRAALL investigators, showed significant benefit in terms of long-term survival in patients who underwent HSCT after reduced intensity chemotherapy plus imatinib.¹

Most physicians are using second- and third-generation TKIs now, and the US Intergroup study from a few years ago looked at dasatinib combined with hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) in Ph+ ALL patients and found that  those who received HSCT had significantly better outcomes in that study also.² I’m hopeful that in the near future there will be conclusive evidence with long-term follow-up that will allow us to eliminate transplant entirely, but we’re not quite there yet. We should also remember that, as physicians at large academic centers, we are able to maintain dose density in a way and give treatments that may not be possible in smaller or community hospitals where some patients are getting treated for Ph+ ALL. However, a transplant ensures that everybody gets a certain level of treatment that seems to be curative much of the time.

Another concern is about salvage. Our ability to get patients back into remission has improved, but in our experience, the long-term outcomes of transplant in a second remission are not good.³ A few years ago, the MD Anderson group also published findings showing that outcomes weren’t good in that scenario.⁴ So salvage, or at least curative salvage, is difficult for these patients.

Dr. Short: I agree with a lot of what Jon said. When imatinib was first introduced, there was a clear benefit to transplant. Even in the most recent SWOG study with hyper-CVAD plus dasatinib, the overall analysis showed improvement for transplant.² But I think the data are probably more nuanced than that. For several years, at my institution, we’ve been using measurable residual disease (MRD) to decide which patients should or should not be transplanted. We have looked at different timepoints and we’ve found that in patients who achieved MRD negativity by PCR for BCR-ABL by approximately three months into treatment and didn’t go on to transplant had a 4-year survival of about 66%.⁵

Although in the global analysis of the SWOG study patients benefited from transplant, the question remains as to whether that benefit was impacted by their MRD response. I suspect that the benefit of transplant is much less in the patients who achieve MRD negativity. I believe we can use MRD to help decide which patients may benefit from transplant. MRD response may also help us to evaluate whether newer therapies may be able to prevent the need for a transplant in first remission.

We have a major paradigm shift in the treatment of Ph+ ALL, with published data on dasatinib plus blinatumomab, which is basically a chemotherapy-free regimen, associated with excellent response rates.⁶ At the latest update, 3-year overall survival (OS) rates were 80%, and about half of those patients went to transplant. That’s significantly lower than other studies in Ph+ ALL, where the large majority of patients have undergone transplant.

Later-generation TKIs could potentially overcome the need for transplant as they become more widely used. Recently we’ve been combining the much more potent TKI ponatinib with blinatumomab. Among 30 patients on that regimen in the frontline setting, only one went to transplant. The estimated 2-year survival is 93% with no relapses observed to date.⁷ In the pre-blinatumomab era, we also looked at hyper-CVAD with ponatinib and only transplanted about 20 to 25% of patients. The 5-year survival rate among patients who had good MRD response and didn’t go to transplant was 83%.⁸

I believe that with the wider use of ponatinib and/or blinatumomab in frontline regimens, we’ll see the proportion of patients who need transplant decrease significantly.

Dr. Webster: That’s a very good point about MRD. Interestingly, many of the studies that have looked at polymerase chain reaction (PCR)-based MRD testing pre-transplant seem to show that patients who are MRD-PCR-positive going into transplant have relatively similar outcomes to those who are MRD-negative.^4,9,10 I believe that makes an argument for transplant’s being able to overcome the persistence of MRD. The big question is, what is the timepoint and what is the MRD cutoff beyond which people may not need transplant at all? I’m hopeful that from the trials going forward where we are looking prospectively at MRD timepoints and have exact cutoffs, we will be absolutely certain who may need a transplant or who may not.

Dr. Short: I agree that if were waiting for randomized studies, then we would continue to go with the transplant as the default option, because we don’t have any randomized studies or even large perspective studies to answer this question. However, we must take all the available evidence into consideration as well as the fact that transplant comes with significant morbidity and potential mortality, as well as being difficult for patients logistically and financially.

Our approach has been to try to avoid transplant as a major priority of therapy in so far as it is safe to do so. Across all leukemias, particularly ALL and including Ph+ ALL, we’ve consistently seen that MRD is a powerful indicator of response to therapy and long-term treatment outcomes. So, we have made the decision to not transplant patients who rapidly achieve MRD negativity, based on the available data.

Overall, I think we can see clearly that the field is moving towards fewer transplants, but how confident we feel about this approach in an individual patient is still difficult to determine. I agree that there are some patients who may benefit from transplant in first remission, but more potent TKIs like ponatinib have revolutionized treatment in many ways, and so the patients who achieve MRD negativity are less likely to require transplant.

What are the remaining questions to be answered to improve outcomes with transplant?

Dr. Webster: The first question is, who is the optimal donor? Much of the data we have is from patients with matched sibling donors, but we’ve seen similar outcomes with unrelated donors. Some studies have even suggested better outcomes with unrelated donors, and that outcomes with haploidentical donors are just as good as or even better than with matched transplant.¹¹ Knowing that everybody has a potential donor makes a big difference.

The second question is about the conditioning regimen. As Nick mentioned, the biggest issue with transplant is that it’s associated with a high rate of morbidity and mortality. Conventional myeloablative transplant, particularly in a Ph+ ALL patient, who tends to be older, is often not going to be tolerable and not even something we consider. Using our reduced intensity conditioning regimen, and with post-transplant cyclophosphamide, which seems to greatly reduce graft-versus-host disease (GVHD), particularly chronic GVHD, we have shown that we can substantially reduce non-relapse mortality in patients and reduce GVHD-associated morbidity.³ Outcomes with reduced intensity conditioning seem to be similar, although this is based on retrospective data.⁹

Dr. Short: How can we continue to further improve outcomes for patients? If we are going to transplant, then we need to decrease the associated mortality. Ph+ ALL is now one of the more curable forms of leukemia, particularly with the novel agents that we now have. We need to ensure that we reduce treatment-related mortality as much as possible. There are many ways in which that can be done, with proper selection of donors and conditioning regimens, as mentioned earlier. For those patients who don’t go to transplant, what is left to improve their outcomes? We still don’t really know the appropriate MRD cutoff in terms of when patients should become MRD-negative to best predict for outcomes or how deep the MRD negativity should be before we feel confident that they’re going to be cured with the treatment we’ve given them alone, without transplant. I think that next-generation sequencing MRD assays, which have a sensitivity of about 10^-6 versus standard PCR for BCR-ABL, which is around 10^-4, may even better select those patients who had a very good response and may be very curable without transplant.

Hopefully, with longer follow-up, we’ll see that ponatinib plus blinatumomab is a curative regimen without transplant. If that is the case, then I think wider adoption of similar approaches will ultimately lead to better outcomes across the board for patients with Ph+ ALL. Even if not used in the same combination, these later-generation TKIs are important. We need to mitigate toxicity, however. For example, with ponatinib, which is a very potent drug, we start with a dose of 30 mg and decrease to 15 mg once patients achieve MRD negativity, because of potential cardiotoxicity and other toxicities with ponatinib, which are dose dependent. Overall, ponatinib seems very safe when given long-term at a dose of 15 mg daily.

I also hope that now we’re moving more toward chemotherapy-free combinations, we’ll see patients do better, because not only are these regimens effective at eliminating the residual leukemia, they also avoid the toxicity associated with intensive chemotherapy, which historically has been the standard of care.

Another way in which we have improved outcomes is to reduce central nervous system (CNS) relapses, which have been a particular problem in Ph+ ALL. A few years ago, we moved away from doing 8 intrathecal treatments to 12. We began doing 12 along with the hyper-CVAD ponatinib study and we haven’t seen any CNS relapses to date. We’ve also used that approach in the blinatumomab-ponatinib study and we’re monitoring that very carefully because we are no longer using the high-dose systemic cytarabine or methotrexate to penetrate the CNS. So far, we have had no CNS relapses in that study either.

If we were to see even one CNS relapse, we might consider intensifying the prophylactic intrathecal chemotherapy. Interestingly, in the D-ALBA trial there were several relapses, about half of which were CNS, even though the investigators reported that they use the same approach of 12 intrathecals, and even though dasatinib supposedly has very good blood brain barrier penetration.⁶ I don’t know how to rationalize these two different experiences. It may be that ponatinib has some CNS penetration and better activity once it’s in the CNS.

Dr. Webster: One thing that can be a little confusing in Ph+ ALL is that some of these patients have lymphoid blast crisis of chronic myeloid leukemia (CML) and that with PCR-based testing you may just be finding BCR-ABL in myeloid cells. That’s the advantage of the clonoSEQ® (Adaptive Biotechnologies) and similar MRD assays where you really are looking at lymphocytes because you’re looking at immunoglobulin heavy chain rearrangements. That’s also going to help move the field forward in terms of thinking about how meaningful MRD is and what the specific timepoints are.

Dr. Short: Anecdotally, as we’ve seen a lot of patients who do not necessarily have a diagnosis of CML lymphoid blast phase, but who clearly have low-level PCR positivity after initial therapy. We’ve started doing next-generation sequencing MRD assessment on them and we see that many are negative by this testing, despite persistent low-level PCR positivity. Now, CML in lymphoid blast phase and Ph+ ALL are very similar diseases, and they it can be hard to distinguish them. If it’s a clear, documented case of CML in lymphoid blast phase, our preference is to still give some amount of chemotherapy. We have a regimen of a hyper-CVD with ponatinib followed by blinatumomab that we use in these patients, and our preference has still been to transplant many of these patients, because an analysis we did of lymphoid blast phase CML showed that they appeared to benefit from transplant, particularly if they had previously received a TKI for CML prior to progressing to lymphoid blast phase.

References

1. Chalandon Y, Thomas X, Hayette S, et al; Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL). Randomized study of reduced-intensity chemotherapy combined with imatinib in adults with Ph-positive acute lymphoblastic leukemia. Blood. 2015;125(24):3711-3719. DOI: 10.1182/blood-2015-02-627935
2. Ravandi F, Othus M, O’Brien SM, et al. US Intergroup study of chemotherapy plus dasatinib and allogeneic stem cell transplant in Philadelphia chromosome positive ALL. Blood Adv. 2016;1(3):250-259. DOI: 10.1182/bloodadvances.2016001495
3. Webster JA, Luznik L, Tsai HL, et al. Allogeneic transplantation for Ph+ acute lymphoblastic leukemia with posttransplantation cyclophosphamide. Blood Adv. 2020;4(20):5078-5088. DOI: 10.1182/bloodadvances.2020002945
4. Kebriaei P, Saliba R, Rondon G, et al. Long-term follow-up of allogeneic hematopoietic stem cell transplantation for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: impact of tyrosine kinase inhibitors on treatment outcomes. Biol Blood Marrow Transplant. 2012;18(4):584-592. DOI: 10.1016/j.bbmt.2011.08.011
5. Short NJ, Jabbour E, Sasaki K, et al. Impact of complete molecular response on survival in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood. 2016;128(4):504-507. DOI: 10.1182/blood-2016-03-707562
6. Foà R, Bassan R, Vitale A, et al; GIMEMA Investigators. Dasatinib-blinatumomab for Ph-Positive acute lymphoblastic leukemia in adults. N Engl J Med. 2020;383(17):1613-1623. DOI: 10.1056/NEJMoa2016272
7. Short NJ, Kantarjian H, Konopleva M, et al. Updated results of a phase II study of ponatinib and blinatumomab for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood. 2021;138(Suppl 1):2298-2301. Abstract 614. DOI: 10.1182/blood-2021-153795
8. Short NJ, Kantarjian M, Ravandi F, et al. Long-term safety and efficacy of hyper-CVAD plus ponatinib as frontline therapy for adults with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood. 2019;134(Suppl 1):283. DOI: 10.1182/blood-2019-125146
9. Bachanova V, Marks DI, Zhang M-J, et al. Ph+ ALL patients in first complete remission have similar survival after reduced intensity and myeloablative allogeneic transplantation: impact of tyrosine kinase inhibitor and minimal residual disease. Leukemia. 2014;28(3):658-665. DOI: 10.1038/leu.2013.253
10. Brissot E, Labopin M, Beckers MM, et al. Tyrosine kinase inhibitors improve long-term outcome of allogeneic hematopoietic stem cell transplantation for adult patients with Philadelphia chromosome positive acute lymphoblastic leukemia. Haematologica. 2015;100(3):392-399. DOI: 10.3324/haematol.2014.116954
11. Gao L, Zhang C, Gao L, et al. Favorable outcome of haploidentical hematopoietic stem cell transplantation in Philadelphia chromosome-positive acute lymphoblastic leukemia: a multicenter study in Southwest China. J Hematol Oncol. 2015;8:90. DOI: 10.1186/s13045-015-0186-5